U.S. patent application number 10/464398 was filed with the patent office on 2003-11-20 for method for administering brain-derived neurotrophic factor to the brain.
This patent application is currently assigned to Chiron Corporation. Invention is credited to Frey, William H. II.
Application Number | 20030215398 10/464398 |
Document ID | / |
Family ID | 27538640 |
Filed Date | 2003-11-20 |
United States Patent
Application |
20030215398 |
Kind Code |
A1 |
Frey, William H. II |
November 20, 2003 |
Method for administering brain-derived neurotrophic factor to the
brain
Abstract
Disclosed is a method for transporting neurologic therapeutic
agents to the brain by means of the olfactory neural pathway and a
pharmaceutical composition useful in the treatment of brain
disorders.
Inventors: |
Frey, William H. II; (White
Bear Lake, MN) |
Correspondence
Address: |
Chiron Corporation
Intellectual Property - R440
P.O. Box 8097
Emeryville
CA
94662-8097
US
|
Assignee: |
Chiron Corporation
Emeryville
CA
|
Family ID: |
27538640 |
Appl. No.: |
10/464398 |
Filed: |
June 18, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10464398 |
Jun 18, 2003 |
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10073658 |
Feb 11, 2002 |
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10073658 |
Feb 11, 2002 |
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09375158 |
Aug 16, 1999 |
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6407061 |
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09375158 |
Aug 16, 1999 |
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08780335 |
Jan 8, 1997 |
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6180603 |
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08780335 |
Jan 8, 1997 |
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08361877 |
Dec 22, 1994 |
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5624898 |
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08361877 |
Dec 22, 1994 |
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08161337 |
Dec 2, 1993 |
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08161337 |
Dec 2, 1993 |
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07879556 |
May 4, 1992 |
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07879556 |
May 4, 1992 |
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07446308 |
Dec 5, 1989 |
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Current U.S.
Class: |
424/45 ; 424/450;
514/1.2; 514/17.6; 514/17.7; 514/54; 514/8.4 |
Current CPC
Class: |
A61K 38/28 20130101;
A61K 38/30 20130101; A61K 38/00 20130101; A61K 9/0085 20130101;
A61K 9/0043 20130101; A61K 38/1825 20130101 |
Class at
Publication: |
424/45 ; 514/12;
424/450; 514/54 |
International
Class: |
A61K 038/18; A61L
009/04; A61K 031/715; A61K 009/127 |
Claims
What is claimed:
1. A method for transporting a brain-derived neurotrophic factor to
the brain of a mammal, comprising: applying a pharmaceutical
composition comprising the brain-derived neurotrophic factor to an
upper third of a nasal cavity of the mammal, wherein the
brain-derived neurotrophic factor is absorbed through a nasal
mucosa and transported to the brain of the mammal.
2. The method of claim 1, comprising applying the pharmaceutical
composition to an olfactory area in the upper third of the nasal
cavity.
3. The method of claim 1, comprising applying the pharmaceutical
composition to a roof of a nose.
4. The method of claim 1, comprising applying the pharmaceutical
composition by employing a tube, a catheter, a syringe, a packtail,
a pledget, a submucosal infusion, or a combination thereof.
5. The method of claim 1, wherein the pharmaceutical composition
comprises a liquid, a powder, a spray, a nose drop, a gel, an
ointment, an infusion, or a combination thereof.
6. The method of claim 1, wherein the pharmaceutical composition
comprises a pharmaceutically acceptable carrier, a lipophilic
micelle, a liposome, or a combination thereof.
7. The method of claim 6, wherein the lipophilic micelle or
liposome comprises a ganglioside, a phosphatidylcholine, a
phosphatidylserine, or a combination thereof.
8. The method of claim 1, wherein the pharmaceutical composition
comprises a substance having an affinity for a receptor site on a
neuron.
9. The method of claim 1, wherein the brain-derived neurotrophic
factor is transported to the brain by way of the mammal's nervous
system instead of through the mammal's circulatory system.
10. The method of claim 9, wherein the brain-derived neurotrophic
factor is transported to the brain by way of an olfactory neural
pathway.
11. The method of claim 10, wherein the brain-derived neurotrophic
factor is absorbed into an olfactory system of the brain.
12. The method of claim 10, wherein the brain-derived neurotrophic
factor is transported through a peripheral olfactory nerve into an
olfactory bulb.
13. The method of claim 1, wherein the brain-derived neurotrophic
factor is transported to a basal forebrain, a prepyriform complex,
a hippocampal formation, an amygdaloid nuclei, a nucleus basalis of
Meynert, a locus ceruleus, a brainstem raphe nuclei, or a
combination thereof.
14. A method for administering a brain-derived neurotrophic factor
to the brain of a mammal, comprising: applying a pharmaceutical
composition comprising an effective amount of the brain-derived
neurotrophic factor to a nasal cavity of the mammal, wherein the
brain-derived neurotrophic factor is absorbed through a nasal
mucosa and transported to the brain of the mammal along a neural
pathway and in an amount effective for promoting growth of a brain
cell, promoting survival of a brain cell, augmenting activity of a
brain cell, providing a protective effect on a brain cell, or a
combination thereof.
15. The method of claim 14, wherein the brain-derived neurotrophic
factor is transported to the brain by way of a nervous system
instead of through a circulatory system.
16. The method of claim 14, wherein the brain-derived neurotrophic
factor is transported to the brain by way of an olfactory neural
pathway.
17. The method of claim 16, wherein the brain-derived neurotrophic
factor is absorbed into an olfactory system of the brain.
18. The method of claim 16, wherein the brain-derived neurotrophic
factor is transported through a peripheral olfactory nerve into an
olfactory bulb.
19. The method of claim 14, wherein the brain-derived neurotrophic
factor is transported to the brain of the mammal in an amount
effective for treating a neurological condition, a brain disorder,
a psychiatric disorder, or a combination thereof.
20. The method of claim 19, wherein treating comprises treating or
preventing brain disease or damage or inhibiting degeneration of
nerve cells in the brain.
21. The method of claim 19, wherein treating comprises providing a
protective effect on brain cells against or treating stroke.
22. The method of claim 19, wherein the condition or disorder
comprises a neurodegenerative disorder, an affective disorder,
nerve damage from a cerebrovascular disorder, or a combination
thereof.
23. The method of claim 22, wherein the affective disorder
comprises depression or mania.
24. The method of claim 22, wherein the neurodegenerative disorder
is Parkinson's disease or Alzheimer's disease.
25. The method of claim 14, wherein the brain-derived neurotrophic
factor is transported to the olfactory system of the brain of the
mammal in an amount effective for treating or preventing a loss of
smell.
26. The method of claim 14, comprising applying the pharmaceutical
composition to an upper third of the nasal cavity.
27. The method of claim 26, comprising applying the pharmaceutical
composition to an olfactory area in the upper third of the nasal
cavity.
28. The method of claim 27, comprising applying the pharmaceutical
composition to a roof of a nose.
29. The method of claim 14, wherein the pharmaceutical composition
comprises a pharmaceutically acceptable carrier, a lipophilic
micelle, a liposome, or a combination thereof.
30. The method of claim 29, wherein the lipophilic micelle or
liposome comprises a ganglioside, a phosphatidylcholine, a
phosphatidylserine, or a combination thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/073,658, filed Feb. 11, 2002, which is a continuation of
U.S. application Ser. No. 09/375,158, filed Aug. 16, 1999, now U.S.
Pat. No. 6,407,061 B1, which is a continuation of U.S. application
Ser. No. 08/780,335, filed Jan. 8, 1997, now U.S. Pat. No.
6,180,603 B1, which is a continuation of U.S. application Ser. No.
08/361,877, filed Dec. 22, 1994, now U.S. Pat. No. 5,624,898, which
is a continuation of U.S. application Ser. No. 08/161,337, filed
Dec. 2, 1993, now abandoned, which is a file wrapper continuation
of prior U.S. application Ser. No. 07/879,556, filed May 4, 1992,
now abandoned, which is a file wrapper continuation of prior U.S.
application Ser. No. 07/446,308, filed Dec. 5, 1989, now abandoned,
which applications are herein incorporated by reference.
FIELD OF THE INVENTION
[0002] The present invention is directed to a method for delivering
neurologic agents to the brain by means of the olfactory neural
pathway and a pharmaceutical composition useful in the treatment of
brain disorders.
BACKGROUND OF THE INVENTION
[0003] Alzheimer's disease is an age-associated neurodegenerative
disorder of the brain. The disorder is characterized
histopathologically by the formation and accumulation of
neurofibrillary tangles and neuritic plaques in the brain. In
particular, pathological changes associated with the disease
extensively affect neurons in the olfactory bulb and its connected
brain structures. Degeneration with loss of neurons has been
observed in the hippocampal formation, amygdaloid nuclei, nucleus
basalis of Meynert, locus ceruleus, and the brainstem raphe nuclei,
all of which project to the olfactory bulb. These degenerative
changes result in the loss of memory and cognitive function. In
addition, there is a major loss of cortical and hippocampal choline
acetyltransferase activity and degeneration of basal forebrain
cholinergic neurons. The loss of odor detection in Alzheimer's
patients has been attributed to necrosis of olfactory epithelium,
olfactory bulbs and tracts and the prepyriform cortex.
[0004] At present, there is no treatment for Alzheimer's disease
which effectively prevents or retards the progressive
neurodegeneration of the brain and the loss of smell and cognitive
decline associated with the illness. Neurotrophic and neuritogenic
factors, such as nerve growth factor (NGF) and gangliosides, have
demonstrated therapeutic effects in animal models and cell cultures
which indicate these substances may be of benefit to patients
afflicted with Alzheimer's disease. See Frey, W. H., II and T. A.
Ala (1988) Progress in Clinical Neuroscience 1:287-303.
[0005] Neurotrophic and neuritogenic factors are agents that affect
the survival and differentiation of neurons in the peripheral and
central nervous systems. These growth promoting factors are
signaling substances that are synthesized in tissues in response to
neurons capable of responding to the factor. They bind to receptors
on the surface of nerve cells to promote neuron survival and in
some cases are incorporated into nerve cell membranes. Studies
further indicate that nerve growth factor (NGF), a class of
polypeptide signaling substances, may be capable of improving
cholinergic functioning, which would prevent injury-induced
degeneration of basal forebrain cholinergic neurons and improve
cognitive functioning. Nerve growth factor (NGF) is known to bind
to receptors on axon terminals, and can be internalized and
retrogradely transported to the cell body of neurons. See M. Seiler
(1984) Brain Res. 300:33-39. Other naturally occurring nerve growth
promoting factors include gangliosides, phosphatidylserine (PS),
brain-derived neurotrophic factor, fibroblast growth factor,
insulin, insulin-like growth factors, ciliary neurotrophic factor
and glia-derived nexin.
[0006] Testing the effectiveness of potentially therapeutic agents
against brain disease in animal toxicity studies and human trials
has been hindered, however, by the inability of existing procedures
to readily deliver adequate levels of the agent to affected areas
of the brain over an extended period of time.
[0007] Some experimental therapeutic agents used in the treatment
of Alzheimer's disease, such as GM-1 ganglioside, can be
administered to the brain through the bloodstream because of their
ability to traverse the blood-brain barrier. However, it is not
clear that effective levels of the ganglioside reach the affected
areas of the brain.
[0008] Other potentially therapeutic agents, such as nerve growth
factor (NGF), are unable to cross the blood-brain barrier and must
be administered to the brain by other means. One such method of
delivery is by an intracerebroventricular pump. Use of such a pump,
however, necessitates invasive surgery which can entail a variety
of medically related complications. Furthermore, administration of
medication by pump does not facilitate selective delivery of
medication solely to those areas of the brain affected by disease.
Consequently, healthy areas of the brain may be adversely affected
by the neurologic agent while some diseased areas may not receive a
high enough level for adequate treatment or testing of a drug.
[0009] An effective method of therapeutic intervention is needed to
prevent and effectively treat brain diseases such as Alzheimer's
disease, Parkinson's disease, nerve damage from cerebrovascular
disorders such as stroke, and ordinary aging. Testing the potential
of various neurologic agents is an important aspect of developing
treatments for neurodegencrative diseases. Since existing methods
of testing possible therapeutic agents and treating brain disorders
are of limited benefit, a goal of the present invention is to
develop a procedure to effectively deliver neurologic agents to the
brain. A particular goal of the invention is to develop a method of
delivering neurologic substances to the brain to augment the level
of activity against brain diseases by naturally occurring
substances. A further goal is to develop a means of selective
delivery of a neurologic agent only to areas of the brain which are
damaged by a brain disorder. Still another objective is to develop
a composition that can cause absorption of the neurologic agent
into olfactory neurons and along the olfactory neural pathway to
damaged neurons in the brain. Another goal is to provide
prophylactic treatment of neurodegenerative diseases and to treat
and/or prevent associated loss of smell.
SUMMARY OF THE INVENTION
[0010] These and other goals are met by the present invention which
is directed to a method to convey therapeutic substances to the
brain for the treatment of neurologic or psychiatric disorders and
a pharmaceutical composition capable of delivering a neurologic
agent to the brain for use in such a method of treatment. More
specifically, the method of medical treatment involves intranasal
administration of a neurologic agent which may be absorbed into the
olfactory system of the brain for the treatment of brain disorders
such as Alzheimer's disease, Parkinson's disease, affective
disorders such as depression and mania, nerve damage from
cerebrovascular disorders such as stroke, and the like.
[0011] According to the method of the invention, a neurologic
substance is administered to the nasal cavity of a patient affected
with Alzheimer's disease or other disease afflicting the brain. The
neurologic factor may be applied alone or in combination with other
substances. Particular formulations may include the neurologic
substance in combination with a pharmaceutically acceptable carrier
and/or components that may facilitate the transfer of the
neurologic agent through the nasal mucosa and/or along the
olfactory neural pathway to damaged nerve cells of the brain.
[0012] The neurologic agent may be administered intranasally as a
powder, spray, gel, ointment, infusion, injection, or drops.
[0013] The method of the invention may employ transneuronal
anterograde and retrograde transport of the neurologic agent
entering through the olfactory system of the brain. Once the agent
is dispensed into the nasal cavity, the agent may transport through
the nasal mucosa by means of the peripheral olfactory neurons into
the olfactory bulb and interconnected areas of the brain such as
the hippocampal formation, amygdaloid nuclei, nucleus basalis of
Meynert, locus ceruleus, and the brainstem raphe nuclei. The agent
alone may facilitate this movement into the brain. Alternatively,
the carrier and/or other transfer-promoting factors may assist in
the transport of the neurologic agent into and along the olfactory
neural pathway.
[0014] Lipophilic substances in the form of micelles may be added
to the pharmaceutical composition to enhance absorption of the
neurologic agent across the olfactory epithelium. Among those
substances that are preferred micellar additives are GM-1
gangliosides and phosphatidylserine (PS), which may be combined
with the neurologic agent either alone or in combination.
[0015] The invention further provides a method for preventing
neurodegenerative disorders. Intranasal administration of nerve
growth promoting factors to peripheral nerve cells of the olfactory
system, a purported entryway for causative agents of brain
diseases, helps protect against disease in these nerve cells and
regenerate injured nerve cells thereby forestalling the subsequent
spread of disease to susceptible areas of the brain.
[0016] The invention is also directed to a pharmaceutical
composition which may be used in the method of medical treatment
and/or prophylaxis. The composition is comprised of a neurologic
agent in combination with a pharmaceutical carrier and/or the
foregoing optional additives which promote the transfer of the
agent within the olfactory system.
[0017] The neurologic agent is the active ingredient of the
composition. It is preferred that the neurologic agent promote
nerve cell growth and survival or augment the activity of
functioning cells. Among those agents that are preferred are
neurotrophic and neuritogenic factors that are similar to naturally
occurring nerve growth promoting substances. Among the preferred
neurologic agents are gangliosides, phosphatylserine (PS), nerve
growth factor (NGF), brain-derived neurotrophic factor, fibroblast
growth factor, insulin, insulin-like growth factors, ciliary
neurotrophic factor, glia-derived nexin, and cholinergic enhancing
factors such as phosphoethanolamine and thyroid hormone T.3. GM-1
ganglioside and nerve growth factor (NGF) are particularly
preferred. One or several neurologic substances may be combined
together.
[0018] A preferred embodiment of the composition is the combination
of an effective amount of nerve growth factor (NGF) protein with a
pharmaceutically acceptable liquid carrier containing an
appropriate amount of micelles comprised of GM-1 ganglioside. GM-1
is thought to act synergistically with nerve growth factor (NGF) to
protect neurons and promote nerve regeneration and repair. See
Gorio et al., (1983) Neuroscience 8:417-429.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The method of the present invention administers a neurologic
agent to the nasal cavity of a human or other mammal for the
testing of potential therapeutic agents against brain disease and
for the treatment of brain disorders such as Alzheimer's disease,
Parkinson's disease, affective disorders such as depression and
mania, nerve damage from cerebrovascular disorders such as stroke,
or ordinary aging. In particular, the method delivers a neurologic
agent to diseased areas of the brain by means of the olfactory
neural pathway. The method may employ a pharmaceutical composition
capable of transporting the neurologic agent to diseased neurons of
the brain.
[0020] The method of the invention may achieve delivery of
neurologic substances to afflicted areas of the brain through
transneuronal retrograde and anterograde transport mechanisms.
Delivery of neurologic agents to the brain by that transport system
may be achieved in several ways. One technique comprises delivering
the neurologic agent alone to the nasal cavity. In this instance,
the chemical characteristics of the agent itself facilitate its
transport to diseased neurons in the brain. Alternatively, the
agent may be combined with other substances that assist in
transporting the agent to sites of damaged neurons. It is preferred
that auxiliary substances are capable of delivering the agent to
peripheral sensory neurons and/or along neural pathways to
dysfunctioning areas of the brain. It is further preferred that the
peripheral nerve cells of the olfactory neural pathway be utilized
in order to deliver the neurologic agent to damaged neurons in
those regions of the brain that are connected to the olfactory
bulb.
[0021] The neurologic agent that is administered by the method of
the invention may be generally absorbed into the bloodstream and
the neural pathway of the mammal. It is preferred that the agent
exhibits minimal effects systemically. It is preferred that a large
enough quantity of the agent be applied in non-toxic levels in
order to provide an effective level of activity within the neural
system against the brain disease. It is further preferred that the
neurologic agent promote nerve cell growth and survival or augment
the activity of functioning cells including enhancing the synthesis
of neurotransmitter substances. Among those agents that are
preferred are neurotrophic and neuritogenic factors that are
similar to or the same as nerve growth promoting substances that
are naturally occurring in the nervous system of a mammal. The
agent may be administered to the nasal cavity alone or in
combination with other neurologic agents. The agent may be combined
with a carrier and/or other adjuvants to form a pharmaceutical
composition. Among the preferred neurologic agents are
gangliosides, nerve growth factor (NGF), phosphatidylserine (PS),
brain-derived neurotrophic factor, fibroblast growth factor,
insulin, insulin-like growth factors, ciliary neurotrophic factor,
glia-derived nexin, and cholinergic enhancing factors such as
phosphoethanolamine and thyroid hormone T.3. Among those agents
that are particularly preferred are GM-1 ganglioside and nerve
growth factor (NGF).
[0022] The method of the invention delivers the neurologic agent to
the nasal cavity of a mammal. It is preferred that the agent be
delivered to the olfactory area in the upper third of the nasal
cavity and particularly to the olfactory epithelium in order to
promote transport of the agent into the peripheral olfactory
neurons rather than the capillaries within the respiratory
epithelium. The invention prefers the transport of neurologic
agents to the brain by means of the nervous system instead of the
circulatory system so that potentially therapeutic agents that are
unable to cross the blood-brain barrier from the bloodstream into
the brain may be delivered to damaged neurons in the brain.
[0023] It is preferred that the neurologic agent is capable of at
least partially dissolving in the fluids that are secreted by the
mucous membrane that surround the cilia of the olfactory receptor
cells of the olfactory epithelium in order to be absorbed into the
olfactory neurons. Alternatively, the invention may combine the
agent with a carrier and/or other substances that foster
dissolution of the agent within nasal secretions. Potential
adjuvants include GM-1, phosphatidylserine (PS), and emulsifiers
such as polysorbate 80.
[0024] To further facilitate the transport of the neurologic agent
into the olfactory system, the method of the present invention may
combine the agent with substances that enhance the absorption of
the agent through the olfactory epithelium. It is preferred that
the additives promote the absorption of the agent into the
peripheral olfactory receptor cells. These peripheral neurons
provide a direct connection between the brain and the outside
environment due to their role in odor detection.
[0025] The olfactory receptor cells are bipolar neurons with
swellings covered by hairlike cilia which project into the nasal
cavity. At the other end, axons from these cells collect into
aggregates and enter the cranial cavity at the roof of the nose. It
is preferred that the neurologic agent is lipophilic in order to
promote absorption into the olfactory neurons and through the
olfactory epithelium. Among those neurologic agents that are
lipophilic are gangliosides and phosphatidylserine (PS).
Alternatively, the neurologic agent may be combined with a carrier
and/or other substances that enhance the absorption of the agent
into the olfactory neurons. Among the supplementary substances that
are preferred are lipophilic substances such as gangliosides and
phosphatidylserine (PS). Uptake of non-lipophilic neurologic agents
such as nerve growth factor (NGF) may be enhanced by the
combination with a lipophilic substance.
[0026] In one embodiment of the method of the invention, the
neurologic agent, may be combined with micelles comprised of
lipophilic substances. Such micelles may modify the permeability of
the nasal membrane and enhance absorption of the agent. Among the
lipophilic micelles that are preferred are gangliosides,
particularly GM-1 ganglioside, and phosphatidylserine (PS). The
neurologic agent may be combined with one or several types of
micelle substances.
[0027] Once the agent has crossed the nasal epithelium, the
invention further provides for transport of the neurologic agent
along the olfactory neural pathway. The agent itself may be capable
of movement within the olfactory system. In particular,
neurotrophic and neuritogenic substances have demonstrated ready
incorporation into nerve cell membranes and an affinity for nerve
cell receptor sites. Indications are that these substances are
naturally synthesized in tissues in response to neural stimulation
and that they subsequently bind to receptors on neurons where they
act as nerve growth promoting factors.
[0028] Alternatively, the neurologic agent may be combined with
substances that possess neurotrophic or neuritogenic properties
which, in turn, may assist in transporting the agent to sites of
nerve cell damage.
[0029] The invention also provides a means for the prevention of
brain disorders particularly in cases where the causative factor
enters the brain through olfactory neurons. It is preferred that
prophylactic treatments be employed where evidence indicates
neuronal degeneration in the olfactory neurons as in the case of
Alzheimer's disease and other related brain disorders. Prophylactic
treatment of brain disease may involve the direct or indirect
application of neurologic therapeutic agents to the olfactory
epithelium. Such agents may be absorbed into the peripheral
olfactory nerve cells to protect those neurons from damage from
neurotoxins and other insults and thereby prevent the spread of a
disease-causing agent into other areas of the olfactory neural
pathway and treat and/or prevent the loss of smell which may be
associated with neurodegenerative diseases and aging. As in the
foregoing methods of treatment, prophylactic therapies may apply
the neurologic agent alone or in combination with a carrier, other
neurologic agents, and/or other substances that may enhance the
absorption of the agent into the olfactory neurons. Potential
neurologic agents include gangliosides, nerve growth factor (NGF),
phosphatidylserine (PS), brain-derived neurotrophic factor,
fibroblast growth factor, insulin, insulin-like growth factors,
ciliary neurotrophic factor, glia-derived nexin, and cholinergic
enhancing factors such as phosphoethanolamine and thyroid hormone
T.3. GM-1 ganglioside and nerve growth factor (NGF) are among those
agents that are particularly preferred for prophylactic treatment
of brain disorders.
[0030] To deliver the neurologic agent to the olfactory neurons,
the agent alone or in combination with other substances as a
pharmaceutical composition may be administered to the olfactory
area located in the upper third of the nasal cavity. The
composition may be dispensed intranasally as a powdered or liquid
nasal spray, nose drops, a gel or ointment, through a tube or
catheter, by syringe, by packtail, by pledget, or by submucosal
infusion.
[0031] The optimal concentration of the active neurologic agent
will necessarily depend upon the specific neurologic agent used,
the characteristics of the patient, and the nature of the disease
or condition for which the treatment is to be used. The neurologic
agent may be used alone or in combination with other substances as
a pharmaceutical composition at such concentrations as 30 .mu.M
GM-1 ganglioside, 3 nM nerve growth factor (NGF), and 300 .mu.M
phosphatidylserine (PS). These concentrations are intended only as
examples and do not exclude the use of other concentrations.
[0032] The invention is further directed to a pharmaceutical
composition comprising an amount of a neurologic agent which is
effective in treating or preventing brain disorders in a mammal,
when administered thereto, in combination with a pharmaceutically
acceptable vehicle such as a liquid or powdered carrier and/or
various optional adjuvants. The pharmaceutical composition is
particularly useful for treating patients with Alzheimer's
disease.
[0033] The neurologic therapeutic agent of the pharmaceutical
composition may be any substance that promotes the survival of
neurons and prevents the further loss of nerve cells. It is
preferred that the agent has minimal systemic effects and augments
the activity of naturally occurring nerve growth promoting factors.
Preferably, the agent acts as a nerve growth promoting factor to
prevent degeneration of neurons to induce regrowth of dendrite and
axons and to augment the function of remaining neurons such as
synthesizing neurotransmitter substances. Among the neurologic
agents that are preferred are nerve growth factor (NGF),
gangliosides, phosphatidylserine (PS), brain-derived neurotrophic
factor, fibroblast growth factor, insulin, insulin-like growth
factors, ciliary neurotrophic factor, glia-derived nexin, and
cholinergic enhancing factors such as phosphoethanolamine and
thyroid hormone T.3.
[0034] The carrier of the composition may be any material which is
otherwise pharmaceutically acceptable and compatible with the
active ingredients of the composition. Where the carrier is a
liquid, it is preferred that the carrier is hypotonic or isotonic
with nasal fluids and within the range of pH 4.5-7.5. Where the
carrier is in powdered form, it is preferred that the carrier is
also within an acceptable non-toxic pH range.
[0035] Among the optional substances that may be combined with the
neurologic agent in the pharmaceutical composition are lipophilic
substances that may enhance absorption of the agent across the
nasal membrane and delivery to the brain by means of the olfactory
neural pathway. The neurologic agent may be mixed with a lipophilic
adjuvant alone or in combination with a carrier. Among the
preferred lipophilic substances are gangliosides and
phosphatidylserine (PS). One or several lipophilic adjuvants may be
combined with the agent. It is preferred that the lipophilic
adjuvant be added as micelles.
[0036] The pharmaceutical composition may be formulated as a
powder, granules, solution, ointment, cream, aerosol, powder, or
drops. The solution may be sterile, isotonic or hypotonic, and
otherwise suitable for administration by injection or other means.
In addition to the neurologic agent, the solution may contain
appropriate adjuvants, buffers, preservatives and salts. The powder
or granular forms of the pharmaceutical composition may be combined
with a solution and with diluting, dispersing and/or surface active
agents. Solutions such as nose drops may contain antioxidants,
buffers, and the like.
[0037] A preferred embodiment of the pharmaceutical composition of
the invention is a micellar suspension of GM-1 ganglioside with an
effective amount of nerve growth factor (NGF) combined with
appropriate amounts of a stabilizer such as microcrystalline
cellulose, a suspending agent such as carboxymethyl cellulose or
hydroxypropyl methylcellulose, an emulsifier such as polysorbate
80, a preservative such as benzalkonium chloride, an antimicrobial
such as phenylethyl alcohol, and a thickener such as dextrose.
[0038] The present invention for a method of administering
neurologic agents useful in the treatment of brain disorders such
as Alzheimer's disease presents several advantages over currently
available methods.
[0039] The method of the present invention prefers the olfactory
neural pathway rather than the bloodstream to deliver agents useful
for the treatment of brain disorders such as Alzheimer's disease
directly to the brain. Use of the olfactory system to transport a
neurologic agent to the brain obviates the blood-brain barrier so
that medications like nerve growth factor (NGF), a protein that
cannot normally cross that barrier, can be delivered directly to
the brain. Although the agent that is administered may be absorbed
into the bloodstream as well as the olfactory neural pathway, the
agent provides minimal effects systemically. In addition, the
invention provides for delivery of a more concentrated level of the
agent to neural cells since the agent does not become diluted in
fluids present in the bloodstream. As such, the invention provides
an improved method of testing potential therapeutic agents against
brain disease and of treating neurodegenerative disorders.
[0040] The method provides an advantage by virtue of the intranasal
administration of the medication. The olfactory system provides a
direct connection between the outside environment and the brain
thus providing quick and ready delivery of neurologic agents for
treatment of neurologic disorders. Moreover, the means of applying
a pharmaceutical composition intranasally can be in a variety of
forms such as a powder, spray or nose drops which obviates
intravenous or intramuscular injections and simplifies the
administration of therapeutic medications. As such, the method of
the present invention is an improvement over present methods of
direct administration of neurologic therapeutic agents, such as the
intracerebroventricular pump.
[0041] The application of a neurologic therapeutic agent to the
nasal epithelium also helps prevent the spread of certain brain
disorders by directly treating peripheral olfactory neurons that
are injured by neurotoxins and other insults. Prophylactic
treatment of these outlying nerve cells helps preclude the entrance
of disease-causing agents into the brain. This method of treatment
is particularly beneficial in cases of Alzheimer's disease where an
environmental factor is suspected of being one of the causative
agents of the disease. Application of a neurologic therapeutic
agent to the olfactory sensory neurons also in part treats and/or
prevents the loss of smell which may be associated with
neurodegenerative diseases and ordinary aging.
[0042] Another advantage of the invention is that it provides
delivery of neurologic agents solely to those areas of the brain
affected by disease while avoiding unwanted treatment of brain
regions which are free of the disease. The method of the invention
employs a neurologic agent or other substance that has an affinity
for neuron receptor sites in order to facilitate delivery of the
agent directly to the brain through the olfactory epithelium.
[0043] The invention will be described with reference to various
specific and preferred embodiments and techniques. However, it
should be understood that many variations and modifications may be
made while remaining within the spirit and scope of the
invention.
EXAMPLE 1
[0044]
1 Formulations of Pharmaceutical Compositions Active Ingredients
Group 1. 30 .mu.M GM-1 ganglioside (GM-1) Group 2. 3 nM nerve
growth factor (NGF) Group 3. 300 .mu.M phosphatidylserine (PS)
Group 4. 30 .mu.M GM-1 3 nM NGF Group 5. 30 .mu.M GM-1 300 .mu.M PS
Group 6. 3 nM NGF 300 .mu.M PS Group 7. 30 .mu.M GM-1 3 nM NGF 300
.mu.M PS
[0045] To formulate an aqueous preparation of the pharmaceutical
composition, one or more of the following substances and/or
carriers may be combined with any one of the aforementioned groups
of active ingredients: microcrystalline cellulose, carboxymethyl
cellulose, hydroxypropyl methylcellulose, polysorbate 80,
benzalkonium chloride, phenylethyl alcohol, and dextrose. The
preparation is to be maintained at a pH between 4.5-7.5. The
concentration of active ingredients may follow the guidelines set
forth above, but does not exclude the use of other concentrations
or active ingredients.
[0046] Alternatively, any one group of the aforementioned active
ingredients may be combined with propellants such as
trichloromonofluoromethane or dichlorodifluoromethane, and
delivered by an aerosol spray or similar application means as a
non-aqueous preparation. Oleic acid may be added to the mixture as
a lubricant.
EXAMPLE 2
Formulating Micelles
[0047] The compositions of Example 1 may further contain micelles
consisting of GM-1 ganglioside and/or phosphatidylserine (PS). To
formulate micelles, the lipid may be exposed to sonication in the
aqueous solution of the pharmaceutical composition.
* * * * *