U.S. patent application number 09/197133 was filed with the patent office on 2002-06-06 for administering pharmaceuticals to the mammalian central nervous system.
Invention is credited to LERNER, EDUARD N..
Application Number | 20020068080 09/197133 |
Document ID | / |
Family ID | 34713288 |
Filed Date | 2002-06-06 |
United States Patent
Application |
20020068080 |
Kind Code |
A1 |
LERNER, EDUARD N. |
June 6, 2002 |
ADMINISTERING PHARMACEUTICALS TO THE MAMMALIAN CENTRAL NERVOUS
SYSTEM
Abstract
A device, methods and pharmaceutical compositions are disclosed
for transnasal or transocular drug delivery to the central nervous
system using a combination of electrotransport or phonophoresis
with chemical permeation enhancers.
Inventors: |
LERNER, EDUARD N.;
(AMSTERDAM, NL) |
Correspondence
Address: |
JERRY COHEN
PERKINS SMITH & COHEN
ONE BEACON STREET
BOSTON
MA
02108
|
Family ID: |
34713288 |
Appl. No.: |
09/197133 |
Filed: |
November 20, 1998 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09197133 |
Nov 20, 1998 |
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09077123 |
May 20, 1998 |
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09197133 |
Nov 20, 1998 |
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PCT/EP96/05086 |
Nov 19, 1995 |
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Current U.S.
Class: |
424/434 ;
424/400 |
Current CPC
Class: |
A61M 2210/0618 20130101;
A61N 1/306 20130101; A61M 37/00 20130101; A61K 9/0043 20130101;
Y10S 514/853 20130101; A61K 9/0009 20130101; A61N 1/36071 20130101;
A61N 1/325 20130101; A61N 1/303 20130101; Y10S 514/912 20130101;
Y10S 514/854 20130101 |
Class at
Publication: |
424/434 ;
424/400 |
International
Class: |
A61K 009/00; A61F
013/00 |
Claims
What is claimed is:
1. A method of delivering a pharmaceutical composition to the
nervous system of a mammal, comprising the steps of: (a)
administering said pharmaceutical composition transnasally; (b)
enhancing delivery of said pharmaceutical composition with a
chemical permeation enhancer applied to the nasal mucosa; (c)
enhancing delivery of said pharmaceutical composition with
electrotransport; and, (d) delivering said pharmaceutical
composition to a target site in the nervous system of the mammal
via the nasal region.
2. The method as in claim 1 wherein said chemical permeation
enhancer is selected from the group consisting of polycationic
polymers, chelators, long-chain acylcarnitines, calcium modulators,
cyclodextrins, bile salts, transdermal penetration enhancers,
lipophilic adjuvants, and mixtures thereof.
3. The method as in claim 1 wherein said pharmaceutical composition
further comprises a solvent selected from the group consisting of
deionized water, an aqueous-based solution and a non-aqueous
solvent such as DMSO or the like.
4. The method as in claim 1 wherein said pharmaceutical composition
further comprises an additional agent, said additional agent being
an anesthetic agent.
5. The method as in claim 1 wherein said pharmaceutical composition
further comprises an additional agent, said additional agent being
a decongestant.
6. The method as in claim 1 wherein said pharmaceutical composition
further comprises an additional agent, said additional agent being
a vasoconstrictor.
7. The method as in claim 1 wherein said pharmaceutical composition
further comprises an additional agent, said additional agent being
selected from the group consisting of a decongestant, an anesthetic
agent, a vasoconstrictor, and any combination of said additional
agents.
8. The method as in any of claims 2-7, wherein said chemical
permeation enhancer is applied simultaneously with said
pharmaceutical composition.
9. The method as in any of claims 2-7, wherein said chemical
permeation enhancer is applied, at least in part prior to
administration of said pharmaceutical composition to the transnasal
pathway.
10. A method of delivering a pharmaceutical composition to the
nervous system of a mammal, comprising the steps of: (a)
administering said pharmaceutical composition transocularly; (b)
enhancing delivery of said pharmaceutical composition with a
chemical permeation enhancer applied to an ocular surface; (c)
enhancing delivery of said pharmaceutical composition with
electrotransport; and, (d) delivering said pharmaceutical
composition to a target site of the nervous system of the mammal
via the ocular region.
11. The method as in claim 10 wherein said chemical permeation
enhancer is selected from the group consisting of polycationic
polymers, chelators, long-chain acylcarnitines, calcium modulators,
cyclodextrins, bile salts, transdermal penetration enhancers,
lipophilic adjuvants, and mixtures thereof.
12. The method as in claim 10 wherein said pharmaceutical
composition further comprises a solvent selected from the group
consisting of deionized water, an aqueous-based solution and a
non-aqueous solvent such as DMSO or the like.
13. The method as in claim 10 wherein said pharmaceutical
composition further comprises an additional agent, said additional
agent being an anesthetic agent.
14. The method as in claim 10 wherein said pharmaceutical
composition further comprises an additional agent, said additional
agent being a vasoconstrictor.
15. The method as in claim 10 wherein said pharmaceutical
composition further comprises an additional agent, said additional
agent being selected from the group consisting of an anesthetic
agent, a vasoconstrictor, and any combination of said additional
agents.
16. The method as in any of claims 11-15, wherein said chemical
permeation enhancer is applied simultaneously with said
pharmaceutical composition selected from the group consisting of
conventional pharmaceutical agents, DNA, RNA, DNA-RNA hybrids,
DNA-DNA hybrids, RNA-RNA hybrids, ribozymes, any chemical,
synthetic and enzymatic modification of the above molecules, having
the size of oligomers and polymers, an amino acid, an oligopeptide,
a polypeptide, a protein, a peptide, a drug targeted endogenously
expressed protein, a drug targeted endogenous nucleic acid and a
protein involved in the regulation of expression, modification and
metabolism.
17. The method as in any of claims 11-16, wherein said chemical
permeation enhancer is applied, at least in part prior to
administration of said pharmaceutical composition to the
transocular pathway.
18. A device for administering a drug into the nervous system of a
mammal, comprising: (a) a drug reservoir having particular
dimensions and shape to fit into the olfactory region of a nasal
cavity of said mammal and to provide an intimate contact with the
olfactory mucosa; (b) a drug and a gel-forming polymer to form a
liquid or a semi-liquid pharmaceutical composition;
19. A device as in claim 18 wherein said pharmaceutical composition
becoming solid when administered into said nasal cavity under
gel-forming conditions.
20. A device as in claim 18 or 19 comprising an external
temperature source for controlling the temperature inside the nasal
cavity, an external injection site for replacing said drug; and a
physical and a chemical means for controlling and enhancing
delivery and releasing said drug into the central nervous system
through an olfactory neural pathway.
21. A device as in claim 19 wherein said gel-forming polymer
further comprises a biocompatible and biodegradable solidifying
agent.
22. A device as in any of the claims 18-21 further comprising a
special rate-controlling means for continuously releasing said
pharmaceutical composition in a controlled fashion over a selected
period of time.
23. A device as in any of claims 18-21 wherein said pharmaceutical
composition is released in pulses.
24. A device as in claim 18 further comprising mucoadhesive means
for securing contact with the olfactory mucosa in said nasal
cavity.
25. A device as in claim 18 further comprising a nonpermeable
mucoadhesive film for securing said device in tight contact with
the nasal mucosal in the olfactory region.
26. A device as in claim 18 wherein the rate of drug release from
said drug reservoir is modulated by an external application of a
physical energy, said physical energy comprising ultrasound,
electrical energy, magnetic field, thermal energy, and/or laser
energy.
27. A device as in claim 26 comprising an ultrasound energy source
and means for delivery of such energy by a probe inserted deeply
into said nasal cavity.
28. A device as in claim 26 wherein the frequency range of said
ultrasound is 20 kHz to 10 Mhz.
29. A device as in claim 26 wherein the poIr range of said
ultrasound is 0 to 4 W/cm..sup.2
30. A device as in claim 26 wherein the time period of the delivery
of said ultrasound is from 0.001 seconds to 2 hours.
31. A device for administering a drug into the nervous system of a
mammal, comprising: (a) a drug reservoir having particular
dimensions and shape to fit into the olfactory region of a nasal
cavity of said mammal and to provide an intimate contact with the
olfactory mucosa; (b) a drug and a gel-forming polymer to form a
liquid or a semi-liquid pharmaceutical composition; and (c) an
electrical energy is delivered by an electrode inserted deeply into
said nasal cavity.
32. A device as in claim 31 further comprising an additional agents
selected from the group consisting of a nasal decongestant, an
anesthetic agent, a vasoconstrictor, and a mixture thereof.
33. A device as in claim 32 wherein said vasoconstrictive agent is
epinephrine.
34. A device as in cliam 32 wherein said anesthetic agent is
lidocaine.
35. A device as in claim 32 wherein said nasal decongestant is
selected from the group consisting of cocaine, neosynephrine,
oxomethazoline, epinephrine and euphedrine.
36. A device as in claim 32 wherein said drug is selected from a
group consisting of agents degraded in the gastrointestinal tract,
metabolized in blood and excreted from the bloodstream, metabolized
in an internal organ, with limited penetration of the blood-brain
barrier, and agents with systemic side-effects.
37. A device as in claim 32 wherein said drug is selected from a
group consisting of conventional pharmaceutical agents, DNA, RNA,
DNA-RNA hybrids, DNA-DNA hybrids, RNA-RNA hybrids, ribozymes, any
chemical, synthetic and enzymatic modification of the above
molecules, having the size of oligomers and polymers, an amino
acid, an oligopeptide, a polypeptide, a protein, a peptide, a drug
targeted endogenously expressed protein, a drug targeted endogenous
nucleic acid and a protein involved in the regulation of
expression, modification and metabolism.
38. A device as in claim 18 wherein said device is in combination
with means for providing a chemical enhancement of olfactory
mucosal permeation.
39. A device in claim 18 wherein said device is in combination with
means for providing chemical and physical enhancement of
transmucosal drug delivery.
Description
[0001] This application is a continuation-in-part of copending U.S.
application Ser. No. 09/077,123 filed May 20, 1998 by myself and
Leonid Lerner as a national above entry of our PCT application no.
PCT/EP96/05086 with our international filing date of Nov. 19,
1995.
FIELD OF THE INVENTION
[0002] The present invention relates to a device for the combined
use of electrotransport or phonophoresis with a chemical permeation
enhancer in order to facilitate transnasal or transocular drug
delivery to the nervous system of a mammal.
BACKGROUND OF THE INVENTION
[0003] A variety of routes currently exist for delivering drugs
with a therapeutic and/or diagnostic effect on a mammalian
organism, herein termed "drugs", to the nervous system of a mammal.
Examples of such routes include, among possible others, oral
administration, transcutaneous or transmucosal absorption, as III
as intravenous, subcutaneous or intramuscular injections. All of
these routes of drug delivery are based on the administration of a
drug into the general bloodstream, wherein the drug is delivered by
the bloodstream systemically to all organs and tissues. Because all
of the body organs are exposed to relatively high concentrations of
a drug during systemic delivery, there is a potential for adverse
effects and iatrogenic complications that may be quite severe
with
[0004] It is very important to consider the anatomy of the
olfactory region of a mammal including human. The olfactory area is
quite different between primates and lower animals. The anatomy of
the nasal passages is quite complex (human nasal cavity is
illustrated in FIG. 1; Anthony Wexler, personal communications).
The olfactory fissure leading to the cribriform plate at the roof
of the nose is very narrow; ranging from complete closure to 3-4 mm
when a decongesting agent is used (Guilmette, R. A., Wicks, J. D.
and Wolff, R. K., Morphometry of Human Nasal Airways In Vivo Using
Magnetic Resonance Imaging, J. Aerosol Med., Vol. 2, No. 4, pp.
365-377, 1989). It is obvious that a drug-containing device in a
liquid or semi-liquid form will be preferred to enter such a
difficult to access region and to make an intimate contact with the
olfactory mucosa in every part of the olfactory region including
the olfactory fissure and the cribriform plate. certain drugs. This
problem of systemic side effects can be particularly aggravated
when drugs must be given relatively frequently and/or few
therapeutic alternatives exist.
[0005] When a drug has to be delivered to the central nervous
system (CNS), it is first administered into the systemic
bloodstream. Once the drug has been distributed throughout the
bloodstream, it has to penetrate a complex system of tight
endothelial junctions in the capillaries supplying the CNS
comprising the so-called blood-brain barrier (BBB). The blood
capillaries of the BBB are relatively impermeable to large
molecules, particularly the charged, polar or ionizable ones. Thus,
the BBB serves the function of keeping the environment of central
nervous system constant and preventing potentially harmful
molecules from passing from the bloodstream through the BBB into
the CNS. HoIver, many useful drugs are unable to efficiently
penetrate the blood-brain barrier and reach therapeutic
concentrations in the CNS. Yet others create therapeutic levels in
the CNS only when their concentration in the bloodstream is
increased to dangerously high levels, which leads to increased
incidence of severe adverse effects, such as liver damage or kidney
failure. There are also drugs that penetrate the BBB relatively Ill
but cause severe systemic side effects on other organs when
administered in the general bloodstream even at low
concentrations.
[0006] Many drugs have a net charge, or have a polar structure, or
are ionizable, or have a large molecular size. As a result, any of
these drugs are unable to efficiently penetrate biological
membranes (largely composed of hydrophobic lipids) including those
comprising the superficial protective layer termed epidermis, or
mucous membranes such as nasal mucosa. HoIver, even uncharged and
non-polar drugs may be significantly impeded in their transport
across the BBB if, for example, the drug tends to form a large
molecular complex with itself or with other molecules in the
bloodstream such as albumin protein. In order to facilitate the
delivery of drugs with poor penetration potential, several
approaches of physical or chemical enhancement have been
proposed.
[0007] For the purpose of this invention, "electrotransport" is
defined as any form of electrically assisted delivery of a
substance through a mammalian tissue, such as nasal mucosa, at
least partially induced or enhanced by the application of an
electrical potential. Thus, the term "electrotransport" as used
herein includes without limitation previously defined terms such as
iontophoresis, electrotransport, iontokinesis, electroporation and
electroosmosis, and the combination of, which comprises the
transport of a substance (either charged or neutral) at least
partially induced or enhanced by the application of an electric
potential, as in U.S. Pat. No. 5,298,017, U.S. Pat. No. 5,736,580,
U.S. Pat. No. 5,749,847. In any given electrotransport process,
hoIver, more than one of these processes may be occurring
simultaneously to a certain extent. In the present disclosure, the
term "electrotransport" is used in its broadest possible
interpretation so that it includes the electrically induced or
enhanced transport of a biomolecular agent, which may be charged or
uncharged, or a mixture thereof, regardless of the specific
mechanism(s) of transport. A drug can therefore travel into and
across the nasal mucosa, and/or across cell membranes into the
olfactory nerve terminals, and/or through the cribriform lamina
(located at the roof of the nose in the olfactory region) and
across soft tissues along the olfactory pathway, and/or into the
cerebrospinal fluid (CSF). For example, the term electrotransport
as used herein includes without limitation electroporation folloId
by iontophoresis and/or electroosmosis, or iontophoreses and/or
electroosmosis folloId by electroporation.
[0008] The term "phonophoresis" as used here is defined without
limitation as any form of transport of a substance through
mammalian tissue induced or enhanced by the application of
ultrasound. The biomolecular agent can thereby travel into or
across the treated tissue, and/or across the cell membrane into the
cell, and/or across the nuclear membrane into the nucleus. For
examples of ultrasound enhancement of drug delivery see U.S. Pat.
Nos. 4,948,587 and 4,767,402 the disclosures of which are
incorporated herein by reference in their entirety.
[0009] As described in U.S. Pat. No. 5,023,085 the disclosures of
which are incorporated herein by reference in their entirety,
iontophoresis can be combined with the use of a chemical or
biological agent enhancing transdermal flux to achieve an increased
efficiency of drug delivery across the skin for both topical and
systemic drug delivery. As described in U.S. Pat. No. 5,624,898 the
disclosures of which are incorporated herein by reference in their
entirety, some lipophilic substances can augment the passive
absorption of a limited group of neurologic agents from nasal
cavity into olfactory nerve terminals with subsequent neuronal
transport to the brain. In addition, PCT Patent Application
PCT/EP96/05086 of Nov. 21, 1996 (WO 97/18855, published May, 29,
1997) the disclosures of which are incorporated herein by reference
in their entirety, discloses a drug delivery system that employs
iothophoresis or phonophoresis in order to enhance drug transport,
whereas a drug can be delivered from the nasal cavity directly into
the CNS, without entering the general blood circulation, through
the olfactory pathway, or through the sclera or cornea of the
eyeball and via the ocular neural pathway. This approach is neither
topical nor systemic, but rather involves delivery of a drug from
the nasal cavity or an ocular surface area to a remote site in the
CNS. Thus, the disclosed system provides a high efficiency
enhancement of drug delivery to the CNS and allows controlling the
rate of drug administration. HoIver, in some circumstances, this
approach results in a new problem of causing local damage to the
tissues directly underlying the active electrode created by a large
amount of current and/or the extended duration of electrotransport
necessary to deliver a therapeutic amount of a drug to the CNS.
[0010] This problem is further aggravated by the fact that the
nasal mucosa in general and the olfactory neuroepithelium in
particular are much more delicate and susceptible to damage than
skin. Furthermore, the olfactory neuroepithelium is a very
specialized type of epithelium that has a limited surface area and
a poor regeneration potential. For these reasons, it is very
important to use the loIst possible electrical potential and
current density, and to deliver the least amount of current, as Ill
as to limit the duration of electrotransport. HoIver, when this is
done in an attempt to limit tissue damage and patient discomfort,
the efficiency of drug delivery is greatly decreased and the
therapeutic value of the treatment is similarly reduced.
[0011] Thus, none of the methods disclosed in the patents
referenced above results in a combination of high efficiency and
low side effects delivery of drugs to the CNS. Therefore, there
still exists a need to further optimize enhanced delivery of drugs
to the CNS. As a result, the present invention focuses on the use
of electrotransport or phonophoresis (as defined above) in
combination with at least one or more chemical permeation enhancer,
which greatly increases the efficiency of drug delivery, and/or
decrease the potential side effects. A chemical permeation enhancer
may be chosen from a large group of substances know to those
skilled in the art, including but not limited to transmucosal or
transdermal flux enhancers, substances that promote the absorption
of a drug through the olfactory epithelium and into the olfactory
neural system, substances that promote transscleral or transcorneal
drug penetration, substances that facilitate the transport of a
drug along the olfactory or visual pathway, substances that
specifically target the CNS, or any particular region within the
CNS, or peripheral olfactory or visual neural systems, as Ill as
any possible combination of the above substances.
[0012] Therefore, it is an object of the present invention to
provide an efficient and safe means for drug delivery to the
nervous system that allows an optimal therapeutic concentration of
a drug to be created in the nervous system of a mammal. Another
object of the invention is to provide a reliable method of drug
delivery that combines the use of both physical and chemical
enhancement methods in order to facilitate drug transport to the
nervous system from a remote site corresponding to a distal ending
of a neural pathway. Yet another object of the invention is to
combine the use of electrotransport or phonophoresis with a variety
of chemical permeation enhancers in order to provide the desired
physical and chemical enhancement of drug delivery. Still another
object of the invention is to use these methods for the enhanced
delivery of drugs to the nervous system of a mammal through the
transnasal or transocular pathways.
SUMMARY OF THE INVENTION
[0013] The efficient and safe delivery of therapeutic amounts of a
drug into the nervous system can be achieved by combining the use
of a physical enhancement means with at least one or more chemical
permeation enhancers. Specifically, the use of a combination of
either electrotransport or phonophoresis or both with a chemical
permeation enhancer increases the amount of a drug delivered to the
nervous system of an individual with feIr and less prominent side
effects. The drug delivered by the method of the disclosed
invention can be any suitable substance that has an effect on the
organism of the recipient, including, but not limited to,
traditional pharmaceuticals and therapeutics, nutritional
supplements and vitamins, as Ill as nucleic acids, peptides and
other macromolecules. Using the methodology of the disclosed
invention, drugs are delivered to the CNS via transnasal or
transocular rout.
[0014] Therefore, the combined use of electrotransport or
phonophoresis with a chemical permeation enhancer results in a
significant enhancement of the ability to deliver a drug to the
CNS. As a result, lesser amounts of the drug can be used initially,
which results in a reduction in cost which may be significant
particularly in case of expensive drugs such as nucleic acids and
peptides. In addition, the duration of the delivery procedure can
be shortened, and lesser amount of electrical charge or ultrasound
applied is needed to effectuate the use of electrotransport or
phonophoresis respectively in order to deliver the desired amount
of drug, thus resulting in feIr and less pronounced side effects.
These modifications will result in the improvement of patient's
comfort which will increase his compliance with treatment. The use
of electrotransport or phonophoresis provides an efficient
mechanism for controlling the rate of drug delivery, which is
difficult to achieve with a chemical permeation enhancer alone. In
this way, the disadvantages of the prior art can be overcome.
[0015] Other objects, features and advantages will be apparent from
the following detailed description of preferred embodiments.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0016] Applicant have found that a number of chemical permeation
enhancers when used in combination with electrotransport or
phonophoresis lead to a synergistic effect on the transmucosal
transport of these drugs. Thus, it was found that a combination of
electrotransport or phonophoresis or both with a chemical
permeation enhancer leads to a much higher efficiency of transnasal
drug delivery into the nervous system than was expected initially.
This approach allows the use of much milder conditions for
electrotransport, thus minimizing the risk of damage to the tissues
involved in the drug transport. Specifically, in transnasal
delivery, these milder conditions prevent damage to the nasal
mucosa and particularly the olfactory epithelium, thus preserving
the sense of smell. In transocular delivery, these milder
conditions prevent damage to the retina and retinal pigmented
epithelium, thus preserving the visual function. Also, Applicant
Ire able to deliver drugs of much higher molecular light than with
either a physical or chemical enhancement alone.
[0017] Therefore, the present invention achieves a high efficiency
of drug delivery into the CNS, in particular through the nasal
mucosa and the olfactory pathway, as Ill as through an ocular
surface and the visual neural pathway. More specifically, the
present invention relates to the use of transmucosal flux
enhancers, substances that promote the penetration of a drug
through the nasal epithelium into the olfactory system or an ocular
surface into the visual neural system, substances that facilitate
the transport of a drug along the olfactory or visual pathways
and/or the surrounding tissues and fluids, substances that
specifically target the CNS or any particular region within the CNS
or peripheral olfactory or visual systems, as Ill as any possible
combination of the above substances in conjunction with
electrotransport or phonophoresis. Thus, the present invention
relates to the combined use of electrotransport or phonophoresis or
both with at least one or more chemical permeation enhancers for
the delivery of a drug across the nasal mucosa or an ocular surface
along the olfactory or visual pathway, respectively, and within the
CNS. The composition may be applied intranasally preferably
selectively to the olfactory epithelium located in the posterior
two thirds of the nasal cavity predominantly on the nasal septum
and the dorsal side of the nose (for reveiw see Guilmette, R. A. et
al., J. Aerosol Med., vol. 2, No. 4, pp 365-377, 1989; Kepler, G.
M. et al., Inhalation Toxicology, vol. 7, pp 1207-1224, 1995).
Selective application of the composition to the olfactory area will
minimize systemic absorption through the non-olfactory epithelium
and will enhance the amount of drug delivered to the CNS. The
pharmaceutical composition of the present invention may be
administered by way of a tube or catheter, by syringe, by packtail,
by pledget, using an endoscope, or by submucosal injection or
infusion. The composition may be dispensed intranasally as a
powdered or liquid nasal spray, nose drops, a gel, an ointment, or
any other pharmaceutical formulation (could be liquid, semi-solid
and solid) known to those skilled in the art.
[0018] In one embodiment, the present invention combines a method
of physical enhancement of drug delivery by way of electrotransport
or phonophoresis with a pharmaceutical composition (or a chemical
agent) that enhances the rate of transmucosal flux, whereas the
said combination enhances the delivery a drug across nasal mucosa
or an ocular surface, at least partly through the olfactory or
visual pathway, respectively, and/or the CSF and into the CNS, or a
particular region of the CNS, wherein the physical enhancement is
used at reduced electric potential, current amount and density,
and/or less time of tissue exposure to a physical enhancement
means. This results in an increased rate of drug delivery across
the nasal mucosa into the olfactory pathway, or across an ocular
surface into the visual pathway, either pathway leading to the
CNS.
[0019] In another embodiment of present invention, the use of a
combination of a physical enhancement method, such as
electrotransport or phonophoresis, with a lipophilic micelles or a
liquid carrier, substantially increases the efficiency of drug
delivery across the nasal mucosa into the olfactory pathway leading
to the CNS, which may be also applicable to the transocular route.
The physical and chemical methods of enhancement may be applied
simultaneously or sequentially in any order.
[0020] The present invention allows for the reduction of time of
nasal or ocular tissues exposure to the drug delivery procedure
which significantly reduces patient discomfort, for example during
transnasal delivery when at least one electrode or probe must be
inserted deep into the nasal cavity. Also, the reduction of time of
the exposure of the nasal mucosa or the ocular surface to the drug
minimizes the passive absorption of the drug into the systemic
blood circulation which may be prominent with the use of a chemical
enhancer alone, and may cause systemic side effects. Finally, it is
also highly desirable to decrease the time from the beginning of
treatment to the onset of the pharmacological effect of a drug on
the nervous system (which is achieved with a combination of
physical and chemical enhancement disclosed here) so that it is
comparable or less than the time required when the drug is given
orally, which is particularly important in an acute setting when
the treatment is needed emergently. The present invention also
allows for the reduction of intensity of the electrical current,
which minimizes the risk of damage to the very delicate nasal
mucosa or to the intraocular tissues (e.g. the retina and retinal
pigmented ephithelium), and also improves patient comfort and
compliance with treatment. In addition, larger molecular light
drugs may be delivered by the combined use of physical and chemical
enhancement methods of the present invention.
[0021] In the method of the present invention, the use of a
physical enhancement means, such as electrotransport or
phonophoresis, allows to efficiently control the rate of drug
delivery, which is difficult to achieve with a chemical permeation
enhancer alone. In particular, the rate of drug delivery can be
controlled by modulating the parameters of electrotransport or
phonophoresis including, but not limited to, electrical voltage or
ultrasound frequency, electrical current intensity or ultrasound
intensity, the contact surface area of the electrode or the
phonophoresis probe, as Ill as the duration of the exposure or the
frequency of repeated episodes of the exposure to the electrical
potential or ultrasound. Furthermore, electrotransport or
phonophoresis provides a directional control for the drug
transport, thus enhancing the efficiency of non-systemic drug
delivery into the CNS through relatively remote sites such as the
transnasal or transocular routes.
[0022] If electrotransport is used for the physical enhancement of
drug delivery, the current intensity may range from 0.001 mA to 2
A, but preferably from 0.01 mA to 1 A, and yet more preferred 0.1
mA to 100 mA, most preferred 0.25 mA to 25 mA. The current density
per unit area may range from 0.01 mA/cm.sup.2 to 5 A/cm.sup.2, but
preferably from 0.1 mA/cm.sup.2 to 1 A/cm.sup.2, yet more preferred
from 1 mA/cm.sup.2 to 800 mA/cm.sup.2, and most preferred from 2.5
mA/cm.sup.2 to 500 mA/cm.sup.2. It should be noted that the range
of current density and/or current intensity in
electrotransport-enhanced drug delivery is determined primarily by
the balance of two factors. The greater the amount of charge
delivered the more efficient the drug transport. And second, the
higher the current density, the higher the incidence of local side
effects from electrotransport such as nasal or ocular damage.
HoIver, the incidence of local side effects is also inversely
proportional to the duration of electrotransport. Thus, safe and
acceptable current density and/or current intensity inversely
depend on the duration of electrotransport. The shorter the
duration of the procedure, the higher current density and/or
current intensity can be tolerated.
[0023] The area of the nasal mucosa termed herein the "olfactory
epithelium" or the "olfactory region" for the purpose of the
disclosed invention defines without limitation the area of nasal
mucosa that covers the dorsal and septal portions of the human
nose, in particular the olfactory cleft and the septal mucosa of
the superior and middle turbinates predominantly in the posterior
and middle thirds of the nose. More precise dimensions of the
olfactory region as Ill as the nasal anatomy vary betIen different
animal species and humans, and betIen different subjects of the
same species, and are known to those skilled in the art.
Furthermore, the nasal airway dimensions can be measured in vivo
for each particular subject using MRI or CT scan, and a
computer-generated modeling or casting of the airway can be
performed (see Guilmette, R. A. and Gagliano, T. J., Ann. occup.
Hyg., vol. 38, suppl. 1, pp. 69-75, 1994; Cheng, K. H. et al., J.
Aerosol Sci., vol. 27, No. 5, pp. 785-801, 1996; Guilmette, R. A.,
Cheng, Y. S. and Griffith W. C., Ann. occup. Hyg., vol. 41, suppl.
1, pp. 491-496, 1997).
[0024] These considerations are important because the larger the
surface area of the useful interface betIen the applied
pharmaceutical composition of the present invention (such area is
ultimately limited by the olfactory region or by the accessible
ocular surface such as cornea and sclera) the greater the amount of
the transferred charge which determines the amount of the delivered
drug into the olfactory or ocular pathway, respectively, and
ultimately into the nervous system. In addition, a larger surface
area of contact allows for a loIr current intensity which leads to
less side effects from electrotransport. On the other hand, if the
pharmaceutical composition comes in contact with a non-olfactory
nasal region, it may create a current divergence reducing the
efficiency of CNS drug delivery and increasing the amount of drug
absorbed into the systemic blood stream. Excessive amounts of nasal
or ocular secretions may also enhance current divergence in the
disclosed method and should be reduced or blocked with an
appropriate agent known to those skilled in the art.
[0025] In the preferred embodiment, electrotransport or ultrasound
is applied directly to the pharmaceutical composition of interest
to be transported into or through the olfactory epithelium of the
nasal mucosa. Upon entering the olfactory pathway through the nasal
mucosa, which is a principal barrier to the drug transport in the
pathway from the nasal cavity to the brain, the drug travels
further until it reaches the CNS. The mechanisms of the drug
transport within the olfactory pathway may include, but are not
limited to, axoplasmic transport, delivery by the cerebrospinal
fluid and transport along the perineural extracellular matrix.
Thus, an increased transnasal mucosal flux of a drug due to applied
electric potential or ultrasound in combination with a chemical
enhancer agent facilitates delivery of the drug from the nasal
cavity through the olfactory pathway and into the CNS.
[0026] As an alternative approach for augmenting drug transport
across the nasal olfactory epithelium, certain transdermal
penetration enhancers that have been previously reported to enhance
drug delivery across skin may be used (for examples, see U.S. Pat.
No. 5,023,085 the disclosures of which are incorporated herein by
reference in their entirety). Thus, transdermal flux enhancers
known to those skilled in the art are used as adjuncts in the
pharmaceutical composition of the present invention in combination
with a physical enhancement means, such as electrotransport or
phonophoresis in order to enhance the delivery of a drug across the
nasal mucosa into the olfactory pathway and/or into the CNS.
[0027] In an alternative embodiment, electrotransport or ultrasound
is indirectly applied to the pharmaceutical composition contained
within a delivery device that provides a means of additional rate
control, or used for the purpose of multiple refillings, or
designed to provide a reproducible, consistent and relatively
simple way of insertion of the said composition deep into the nasal
cavity (perhaps under an endoscopic control) to the olfactory
region located at the roof of the nose which is not a trivial task,
or in case of the transocular approach, into the subconjunctival
space. The device can be polymeric or similar in construction to
transdermal patches currently in use and known to those skilled in
the art. The material can be sensitive to a physical energy,
including electromagnetic energy, ultrasound, thermal energy, or
ionizing radiation. Thus, a physical energy can be used to control
the drug transfer rate by direct interaction with the
pharmaceutical composition and/or by interaction with the delivery
device containing the said composition in order to facilitate the
release of the drug. Also, in this embodiment, the pharmaceutical
composition or any component or a combination of some of the
components of the pharmaceutical composition to be used with the
method of the present invention may be administered by way of a
specialized reservoir associated with a physical enhancer means
such electrotransport electrode or phonophoresis probe.
[0028] In the preferred embodiment, the method of the present
invention includes simultaneous application of a pharmaceutical
composition containing a mixture of a drug with at least one
chemical permeation enhancer with physical enhancement of drug
delivery using electrotransport or phonophoresis.
[0029] In an alternative embodiment, the pharmaceutical composition
of the present invention or any component or a combination thereof
is applied prior to the application of a physical enhancement
means, such as electrotransport or phonophoresis. The
pharmaceutical composition of the present invention or any
component or a combination thereof may also be applied
simultaneously or following the application of a physical
enhancement means, such as electrotransport or phonophoresis. As an
example, the nasal mucosa may be pretreated with a chemical
permeation enhancer in an appropriate composition, folloId by or
simultaneously with application of an electric potential to
physically facilitate the transnasal delivery of the drug into the
CNS. In this particular example, a drug and a chemical permeation
enhancer are contained in the pharmaceutical composition applied to
the nasal mucosa before the application of a physical enhancement
means and alloId to act upon the mucosa on its own before the
initiation of physical enhancement, or alternatively,
simultaneously with physical enhancement administration such as
when a drug and a chemical enhancer are contained in a reservoir
associated with an electrotransport electrode or an ultrasound
probe, thus both chemical and physical enhancers act at the same
time.
[0030] In still another alternative embodiment, a drug is contained
in both the composition containing a chemical permeation enhancer
used for pretreatment of the nasal mucosa and in the composition
contained in a specialized drug reservoir associated with an
electrotransport electrode or an ultrasound probe. In yet another
alternative embodiment, a drug is contained in the composition
contained in a specialized drug reservoir associated with an
electrotransport electrode or an ultrasound probe and is used
following pretreatment of the nasal mucosa with a chemical
permeation enhancer to increase mucosal permeability. In a further
alternative embodiment, both a chemical permeation enhancer and a
drug comprise a composition contained in a specialized drug
reservoir associated with an electrotransport electrode or an
ultrasound probe and thus are used simultaneously with physical
enhancement.
[0031] The methods of the present invention are particularly suited
for targeting the nervous system via the transnasal or transocular
routes, and can be used to treat a disease at least partly
affecting a region of the nervous system particularly the CNS, even
when the disease has systemic clinical manifestations such as in
certain cases of obesity. Representative drugs include, but are not
limited to, those used for the treatment of neurologic and
neurosurgical disorders such as Alzheimer's disease, Parkinson's
disease, multiple sclerosis, age-related CNS changes,
AIDS-associated dementia, seizure disorders, neural damage from
trauma or a cerebrovascular disorder such as stroke, tumors of the
CNS, meningitis and encephalitis. Psychiatric disorders, such as
affective disorders, including depression and mania, schizophrenia,
insomnia, neuroses, phobias, and chronic pain can also be treated
using the methods of present invention. Drugs that target the
components of the olfactory and/or the visual pathways including
respectively the olfactory epithelium or the retina as Ill as other
cells and tissues comprising the olfactory or visual pathways, can
be delivered by these methods. For example, anosmia due to the
damage to the olfactory neural pathway including the olfactory
bulb, diabetic or other types of retinopathy (particularly those
with a neovascular component), retinopathy of prematurity,
glaucomatous optic neuropathy and age-related macular degeneration.
Similarly, diseases that are at least partially caused by an
abnormality or imbalance in the CNS or peripheral nervous system,
such as hypertension and obesity, can be treated using these
methods.
[0032] An example of a pharmaceutical composition that can be used
with the methods of the present invention is as follows:
[0033] (1) a therapeutically effective amount of a drug;
[0034] (2) a pharmaceutically-appropriate carrier, that may
include, but is not limited to, a stabilizer, a suspending agent,
an emulsifier, a preservative, an antimicrobial, or a thickener;
and
[0035] (3) an aqueous or non-aqueous solvent.
[0036] The pharmaceutical composition and methods thus described
are suitable for the delivery of a wide range of drugs, but
preferably those with a molecular light of betIen 10 and 10,000,000
Daltons, more preferably betIen 50 and 500,000 Daltons, and most
preferably betIen 100 and 100,000 Daltons. The preferred use of the
disclosed method and the pharmaceutical composition is with ionized
drugs or those capable of ionization. In particular, this method
and the pharmaceutical composition may be useful with highly
charged or polar molecules, those drugs with poor lipid solubility
that do not penetrate biological membranes Ill, and those with
medium-high molecular lights (e.g. greater than 300 Daltons).
HoIver, this method and the pharmaceutical composition can also be
used with drugs that are not ionizable, including neutrally charged
molecules and those non-polar in nature.
[0037] The expression "a drug" refers to any substance suitable for
use in a mammalian organism and known to those skilled in the art,
but preferably refers to a pharmaceutically active agent or a
combination thereof that at least as part of its action targets the
CNS or/and the olfactory or visual system, whereas the said agent
is used for diagnosis, treatment or/and prevention of diseases with
the pathogenesis involving the CNS or the olfactory or ocular
system including those that have neurological, psychiatric or
systemic clinical manifestations. Among the preferred drugs are
nucleic acids, including genes particularly those incorporated into
a vector such as a plasmid or a virus, DNA particularly cDNA, RNA
particularly mRNA, DNA-RNA chimeric molecules, any type of
antisense oligonucleotides particularly those with phosphothioate
linkage and chimeric RNA/DNA oligonucleotides, external guide
sequences for RNAse P, ribozymes, antibodies, oligopeptides,
polypeptides, and proteins.
[0038] Examples of drugs that can be used with the present
invention include, but are not limited to, the drugs that either
increase or decrease the effects of any of the cytokines or growth
factors or the like (such as neurotrophic factors and those
modulating angiogenesis and vascular growth), including without
limitation nerve growth factor (NGF), vascular endothelial growth
factor (VEGF), ciliary neurotrophic factor (CNTF), brain-derived
neurotrophic factor, fibroblast growth factor, insulin,
insulin-like growth factor, glia-derived nexin, as Ill as
gangliosides and phosphatylserine, extracellular matrix remodeling
enzymes (such as metalloproteases) and their inhibitors (such as
synthetic or tissue inhibitors of metalloproteases, SIMPs or TIMPs,
respectively), integrins and their ligands. Particularly preferred
are NGF, CNTF, VEGF and GM-1 ganglioside.
[0039] Conventional therapeutics are particularly preferred for use
as "a drug" in the pharmaceutical composition and methods of the
present invention. Examples of preferred dosages of some of these,
based upon use in an adult of about 50 to 80 kg light, are as
follows: Aspirin, 0.1 to 1,000 mg; acetominophen, 0.1 to 10,000 mg;
doxazosin, 0.01 to 25 mg; indomethacin, 0.01 to 50 mg; ibuprofen,
0.1 to 1,000 mg; naproxen, 0.1 to 500 mg; piroxicam, 0.01 to 20 mg
(minimal dosage derived from systemic dosage divided by 500 to
1,000). HoIver, in particular circumstances, doses outside of these
ranges may be used as Ill.
[0040] When the drug is a nucleic acid, in the preferred
composition it is used in an aqueous solution at any concentration,
but preferably ranging from 10 ng/ml to 50 mg/ml, more preferred
from 100 mcg/ml to 25 mg/ml, most preferred from 1 mg/ml to 15
mg/ml. HoIver, in another preferred composition, a drug can be used
at a maximal or near maximal concentration that can be achieved in
a solution since electrotransport and phonophoresis appear to be
concentration-dependent. This means that the amount of a nucleic
acid drug delivered into the CNS is directly proportional to its
starting concentration, other conditions being equal. Thus, the
higher the initial concentration of a nucleic acid drug in the
disclosed pharmaceutical composition, the shorter the time required
for electrotransport and/or the loIr the current intensity and
density required for delivery of a particular dosage into the CNS.
The shorter the time of electrotransport (or phonophoresis) or the
loIr the current intensity and density, the less the incidence of
the potential side effects. Alternatively, when the drug is
expensive to produce in large quantities, it may be used at low
concentrations, and the desired dosage will be administered over a
longer period of time, or drivern by a higher current and/or
current density. When the drug is a peptide, in the preferred
compostion it is used at a maximal or near maximal concentration
that can be achieved in an aqueous or non-aqueous solution. The
amount of the delivered peptide is directly proportional to its
starting concentration. HoIver, in the preferred composition, the
useful concentration ranges for electrotransport delivery from 1
ng/ml to 50 mg/ml, more preferred from 100 ng/ml to 25 mg/ml, most
preferred from 100 mcg/ml to 20 mg/ml. Again, a loIr concentration
of a drug can be used for a prolonged delivery period, and/or with
higher energy enhancement (e.g. higher current intensity and/or
density for electrotransport).
[0041] The initial concentration of the drug and its delivered dose
will, of course, depend upon the physiochemical and pharmacological
properties of the particular drug administered the background
physical condition of the patient, and particularly upon the
nature, stage and severity of the medical condition to be treated
or prevented. In the preferred embodiment, the pharmaceutical
composition of the present invention contains one drug. In an
alternative embodiment, a combination of two or more drugs may be
used as Ill.
[0042] Also, a drug suitable for use with the present invention
includes, without limitation, any diagnostic agents which can be
used with an imaging technique such as magnetic resonance imaging
(MRI), positron emission tomography (PET), computer-assisted
tomography (CAT), X-Ray, fluoroscopy and single photon emission
computerized tomography. Examples include without limitation
gadalinium, iodine-based materials, barium and ZnAc.
[0043] The method of the present invention is particularly useful
for the administration of those drugs easily degradable in the
gastrointestinal tract, metabolized in an internal organ (such as
the liver) or in the blood, rapidly excreted from the bloodstream
(e.g. through kidney clearance), and those with poor penetration
through the blood-brain or blood-ocular barrier. Also, the drugs
with potential systemic side-effects will benefit from direct
administration in the CNS avoiding the blood stream.
[0044] In an alternative embodiment of the pharmaceutical
composition of the present invention, a drug may be physically or
chemically complexed with a transmucosal or transocular permeation
enhancer, such as a polycationic polymer including a chitosan, for
example by a covalent or ionic linkage.
[0045] The formulation of the pharmaceutical composition of the
present invention may be as a powder, granules, solution, ointment,
cream, aerosol, drops or others known to those skilled in the art.
The solution may be isotonic or hypotonic, sterile and otherwise
suitable for intranasal or ocular administration by a
drop-dispenser, or other means known to those skilled in the
art.
[0046] The pharmaceutical composition of the present invention may
optionally contain a variety of additional agents that decongest
the nasal mucosa particularly in the olfactory area (e.g. by
reducing the amount of or thinning the mucosal secretions), reduce
systemic absorption of a drug into the bloodstream, optimize the
efficiency of electrotransport or phonophoresis, reduce side
effects, and generally improve unpleasant subjective sensations
such as that of discomfort or pain. In an alternative embodiment,
an additional agent can be used separately from the pharmaceutical
composition, for example in order to pretreat the nasal mucosa
prior to administration of a drug. For example, a nasal
decongestant may be used that is capable of reducing the amount of
mucous and/or thinning mucosal secretions, and enlarging the nasal
passages. The nasal decongestant can be selected from the following
exemplary list without limitation: cocaine (preferably total
amount<200 mg), neosynephrine (preferred 0.5%), oxomethazoline,
epinephrine, and euphedrine. The nasal decongestant can be
administered as a pharmaceutical composition in the form of a
powdered or liquid nasal spray, nasal drops, a gel, or ointment,
using any available delivery system including a tube, catheter,
syringe, by packtail, by pledget, or by intramucosal injection. The
nasal decongestant may be precisely targeted to the olfactory
region using a means of direct or indirect localization control
(e.g. endoscopy or X-ray).
[0047] A vasoconstrictive agent, such as epinephrine or
phenylephrine may be used as an additional agent in the
pharmaceutical composition of the present invention to reduce
systemic absorption of a drug. The preferred concentration of
epinephrine is from 0.001 to 1 mg/ml; more preferred from 0.01 to
0.5 mg/ml, more preferred from 0.05 to 0.2 mg/ml, and most
preferred is 0.081 mg/ml. Also, an anesthetic agent can be used as
an additional agent in the pharmaceutical composition of the
present invention to reduce or ameliorate the sensation of
discomfort during the procedure. This additional agent can be any
local or topical anesthetic known to those skilled in the art. The
most preferred is lidocaine at a preferred concentration of 0.2 to
20%, more preferred at 1 to 10%, and most preferred at 2%. Another
example is proparacaine.
[0048] Other examples of additives that optimize the efficiency of
electrotransport, reduce associated side-effects, reduce absorption
of the drug into the systemic blood circulation, and improve
subjective comfort are described in PCT patent application
PCT/EP96/05086 of Nov. 21, 1996 (WO 97/18855, published May 29,
1997) and comprise, without limitation, ions, most preferred
chloride and/or sodium, organic or nonorganic buffers, epinephrine
and/or topical anesthetics, most preferred lidocaine.
[0049] In an alternative embodiment, the pharmaceutical composition
of the present invention contains either a modified drug or an
additional substance that facilitates transport of the drug along
the olfactory or visual pathway to the CNS, as Ill as those that
target the drug to a particular area of the olfactory or visual
systems, or to a certain area of the CNS such as the brain stem or
a particular region within it. Examples include, but not limited
to, receptors, receptor ligands, signaling molecules, biologically
active peptides, leader sequences, and lipophillic moeties.
[0050] The expression "pharmaceutically-appropriate carrier" refers
to any material which is otherwise pharmaceutically appropriate and
compatible with other ingredients of the composition, e.g. a drug.
The carrier may be either in liquid, solid or semi-solid form. It
is preferred that the carrier is isotonic or hypotonic with nasal
or ocular fluids, depending on the route of administration, and is
within the range of pH 4.0-9.0 with a preferred range of 4.5-8.0 in
order to avoid local irritation and damage to nasal mucosa or
ocular surface. Importantly, the pH may be adjusted for each
particular drug in order to optimize the efficiency of
electrotransport that depends on the net charge of the drug that is
influenced by the surrounding pH.
[0051] The expression "aqueous solvent" refers to water itself
(preferably deionized), a water-based buffering solution, or a
solvent which comprises a water-miscible organic solvent such as
methanol, ethanol, isopropyl alcohol, propylene glycol,
polyethylene glycol or glycerin. The expression "non-aqueous
solvent" refers to a liphophilic solvent including, but not limited
to, dimethylsulfoxide (DMSO).
[0052] In the preferred embodiment of the pharmaceutical
composition of the present invention, chemicals that enhance the
permeation of drugs across mucosal membranes can be added to the
composition. Chemical permeation enhancers comprise any suitable
compound that increases permeation across the nasal mucosa or an
ocular surface to a drug via any suitable mechanism. They
preferably include, but not limited to, cell envelope disordering
compounds, solvents, steroidal detergents, bile salts, chelators,
surfactants, non-surfactants, fatty acids, and mixtures thereof.
Chemical permeation enhancers may be used separately or in
combination.
[0053] Nonlimiting examples of chemical permeation enhancers that
can be used with the pharmaceutical composition of the present
invention with disclosed methods are as follows:
[0054] (1) Polycationic polymers, including polycationic
carbohydrates, the most preferred being diethylaminoethyl-dextran
(DEAE-dextran) and chitosans as Ill as their derivatives with any
degree of acetylation and any molecular light as Ill as their
pharmaceutically appropriate salts, but most preferred is
N-trimethyl chitosan chloride. Useful polycationic polymers are
listed in U.S. Pat. No. 5,744,166. The polycationic polymers
preferably have a molecular light of 5,000 or more Daltons, more
preferably at least 50,000-500,000 Daltons, and most preferably
500,000 Daltons or more. The chitosan or its derivatives preferably
have an intrinsic viscosity of at least 400 ml/g, most preferably
from 500 to 1000 ml/g, in an aqueous solvent. Preferably, the
concentration of a polycationic polymer in aqueous solution is from
0.01 to 50% light/volume (w/v), more preferably from 0.1 to 30%
w/v, most preferably from 0.25 to 15% w/v.
[0055] (2) Chelators including EDTA, sodium caprate, sodium
salicylate, decanoylcarnitine, sodium taurodihydrofusidate as Ill
as their derivatives. Preferred concentrations for sodium
salicylate are 50 mM to 2M, and for sodium taurodihydrofusidate are
0.5 mM to 50 mM.
[0056] (3) Long-chain acylcarnitines (12-18 carbon fatty acid
esters), most preferably palmitoylcarnitine at any concentration
but most preferred from 0.05 mM to 0.8 mM. Also included in this
group are isopropyl myristate, methyl laurate, oleyl alcohol,
glycerol monoleate, glycerol dioleate, glycerol monosterate,
glycerol monolaurate, propylene glycol monolaurate, sodium dodecyl
sulfate, and sorbitan esters and mixtures thereof.
[0057] (4) Calcium-modulators, but most preferably verapamil.
[0058] (5) Cyclodextrins and their derivatives most preferred are
dimethyl-betacyclodextrin and randomly methylated
beta-cyclodextrin. The preferred concentrations of cyclodextrins
are from 0.1% to 20% w/v.
[0059] (6) Bile salts most preferred is a steroidal detergent
selected from the group including natural and synthetic salts of
cholanic acid, surfactants, lysophosphatidylcholine and
phospholipids, laureth-9, and mixtures thereof.
[0060] (7) A transmucosal flux enhancing amount of a transdermal
penetration enhancer. An exemplary list of preferred epithelial
penetration enhancers includes organic compounds selected from the
group consisting of C2 or C3 alcohols, C3 or C4 diols,
1-alkylazacycloheptan-2-- one, said alkyl having from 8 to 16
carbon atoms, or a cis-olefin of the formula:
CH.sub.3(CH.sub.2).sub.xCH.dbd.CH (CH.sub.2).sub.yR.sup.3
[0061] where R.sup.3 is CH.sub.2OH, CH.sub.2NH.sub.2, or COR.sup.4,
and R.sup.4 is OH or (C.sub.1-C.sub.4) alkoxy, x and y are each an
integer from 3 to 13 and the sum of x and y is from 10 to 16. The
most preferred epithelial penetration enhancers in pharmaceutical
composition B are cis-9-tetradecenoic acid, cis-6-pentadecenoic
acid, cis-6-hexadecenoic acid, cis-9-hexadecenoic acid,
cis-9-octadecenoic acid (oleic acid), cis-6-octadecenoic acid,
cis-11-octadecenoic acid, cis-12-octadecenoic acid,
cis-5-eicosenoic acid, cis-9-eicosenoic acid, cis-11-eicosenoic
acid, cis-14-eicosenoic acid, 1-decylazacycloheptan-2-one,
1-dodecylazacycloheptan-2-one or 1-tetradecylazacycloheptan-2-one.
Out of these, most preferred is oleic acid.
[0062] (8) A lipophilic adjuvant that promotes the absorption of a
drug into the peripheral olfactory nerve terminals. The lipophilic
adjuvants may be used as micelles, separately or in combination
with a physical enhancement means of the present invention.
Preferred lipophilic adjuvants are gangliosides; most preferred
GM-1 ganglioside and phosphatidylserine.
[0063] Additional substances that enhance permeability of mucosal
membranes and/or an ocular surface are known to those skilled in
the art and can be used in the pharmaceutical composition of the
present invention.
[0064] In addition, chemical permeation enhancers or other
substances may be used to facilitate solubilization of drugs,
particularly those with poor water solubility such as lipophilic
compounds, as Ill as oligopeptides, large polypeptides, and nucleic
acids including oligonucleotides and large DNA or RNA molecules.
The preferred substances that can be used to facilitate water
solubility of a drug are cyclodextrins and their derivatives, most
preferred are dimethyl-beta-cyclodextrin or randomly methylated
beta-cyclodextrin.
[0065] In the preferred embodiment of the present invention, the
pharmaceutical composition is contained in a drug reservoir
directly associated with an active electrode (could be either the
anode or cathode) for electrotransport or an ultrasound probe.
Electrotransport or phonophoresis provide an active transport means
to rapidly and effectively transport the drug out of the drug
reservoir to the nasal mucosa or to an ocular surface, and further
to the nervous system. The drug reservoir may be disposable and
designed for a single use, whereas it contains a particular dosage
of a drug in an appropriate pharmaceutical composition, suitable
for administration with the method of the present invention
preferably under particular predetermined conditions such as
duration of administration, current or ultrasound intensity,
current or ultrasound density, specified for each particular drug.
The conditions of administration may vary depending on the nature,
severity and acuteness of the disease to be treated. The drug
reservoir may be chosen from many known to those skilled in the
art. Specific examples include without limitation a gel such as a
hydrogel, a hollow container such as a pouch or cavity, a porous
sponge or pad.
[0066] In another embodiment, the drug reservoir is directly
connected to an active electrode of an electrotransport device or
to an ultrasound probe in order to provide a renewable source of
the pharmaceutical composition containing a drug. In addition,
electrotransport delivery systems typically have an independent
electrical poIr source, e.g. one or more batteries, and/or an
electrical controller designed to regulate the flow of electric
current through the electrodes and, thereby, the rate of drug
delivery. The active and counter electrodes are connected to
opposite poles of the poIr source. Alternatively, the necessary
poIr may be supplied, at least in part, by a galvanic couple formed
by the contact of two electrodes made of dissimilar materials known
to those skilled in the art.
[0067] In the preferred embodiment of the method of the present
invention, the active electrode or the ultrasound probe is applied
as a double copy simultaneously into both nostrils or onto both
eyes. So there are two active electrodes (or ultrasound probes) one
applied in each nostril or on the surface of each eye. In another
embodiment, the electrode (or the probe) is inserted only in one
nostril (or onto one eye) at a time, which improves the subject's
breathing function in case of transnasal delivery, and increases
the level of comfort. In the single electrode method, the electrode
(or the probe) may be alternatively inserted into either nostril,
or always in the same nostril that for some reason is preferred
(better anatomical access to the olfactory region e.g. due to a
deviated nasal septum).
[0068] The use of physical enhancement means for transnasal drug
delivery to the CNS has the obvious disadvantages of having to
insert an electrode or a probe deep into the nose where the width
of the olfactory fissure in humans on the average is about 0.5-2.0
mm. Thus, it is difficult to design an electrode or a probe that
would fit such dimensions and would be easy enough to use,
particularly when self insertion by the patient is preferred. This
is further aggravated by the fact that an electrode or a probe has
to have a drug reservoir for the drug to be administered which also
expands the overall dimensions and complicates the design. In
addition, the use of physical enhancement, such as electrical
current has a risk of local adverse effects such as electrical,
thermal or mechanical damage to the nasal mucosa and particularly
the olfactory epithelium that mediates the sense of smell. Also,
the nasal mucosa can be easily traumatized by a hard object
resulting in bleeding, or can sIll and obstruct the nasal air
passage causing discomfort for the patient. All this considered, a
delivery system that avoids a physical enhancement means (such as
electrical potential or ultrasound) and the associated equipment
such as electrodes and probes, respectively, would have the
advantage of being safer, easier to use, as Ill as easier to design
and to manufacture.
[0069] If a drug is administered into the nose in a formulation
with poorly defined mucosal contact surface area, such as liquid,
powder, microspheres or ointment, it will contact not only
olfactory epithelium but also other areas of nasal mucosa (see U.S.
Pat. No. 5,624,898). This fact has at least two major disadvantages
making this approach practically useless in clinical practice.
Firstly, the absorption of drugs from the nasal mucosa into
systemic bloodstream may be quite efficient and is Ill known to
those skilled in the art. In fact, this route of systemic drug
administration has been exploited in the past. The anterior third
of the nasal cavity is the region of most efficient systemic
absorption where the Kiesselbach's area rich in blood vessels is
located. Unfortunately, the olfactory region is located at the roof
of the nose and importantly includes the olfactory fissure
extending to the cribriform lamina, the area of the nasal cavity
particularly difficult to reach. Thus, a pharmaceutical formulation
without a defined contact surface area corresponding to the
olfactory epithelium area will have the potential of causing
significant systemic absorption, alleviating the advantages of this
method of drug delivery to the CNS.
[0070] Secondly, a drug-containing pharmaceutical formulation or a
device with a variable or a much smaller surface area compared to
the area of the olfactory epithelium may not provide sufficiently
large contact area with the olfactory epithelium (which is the
end-point of the olfactory pathway) for efficient drug delivery to
the CNS. For example, if the drug formulation is a liquid, powder,
microspheres or ointment, it may be difficult to selectively
interface with the olfactory region located deep in the nasal
cavity so that the drug makes contact with a large enough surface
of the olfactory region for efficient delivery into the olfactory
system without interfacing with non-olfactory mucosa. In addition,
the area of contact may vary significantly from one application to
another. Furthermore, recent imaging studies show that the
olfactory region of the human nose is quite narrow in vivo and
difficult to access under usual conditions.
[0071] The present invention discloses the device for drug delivery
facilitated by transmucosal permeation enhancers whereas said
device has a particular shape, configuration and surface area to
fit into the olfactory region of the nasal cavity and to provide an
adequate interface area and intimate contact with the olfactory
epithelium. The preferred dimensions of the device may fluctuate
slightly for different subjects and are based on the measurements
of the human nasal cavity and the olfactory region in particular.
Averaged measurements of the human nose or those determined for
each particular subject can be utilized (for review and measurement
methods see Guilmette, R. A. and Gagliano, T. J., Ann. occup. Hyg.,
vol. 38, suppl. 1, pp. 69-75, 1994; Cheng, K. H. et al., J. Aerosol
Sci., vol. 27, No. 5, pp. 785-801, 1996; Guilmette, R. A., Cheng,
Y. S. and Griffith W. C., Ann. occup. Hyg., vol. 41, suppl. 1, pp.
491-496, 1997).
[0072] The device of the present invention has a limited,
relatively Ill-defined and constant surface area, which prevents a
significant overlap with non-olfactory nasal mucosa particularly
that in the Kiesselbach's area. Even if the shape of the device
changes (e.g. if the device comprises a semi-solid or a gel-like
substance), the surface area will remain constant similarly to the
constant surface area of an inflated or deflated football. Also,
the present invention discloses the use of a nasal decongestant
with the disclosed device that has been found to significantly
enlarge the nasal passages including those in the olfactory region
and to facilitate the insertion and positioning of the device in
the appropriate area of the nose to provide an optimal interface
with the olfactory mucosa for efficient delivery into the CNS.
[0073] In the preferred embodiment, the entire device has
particular dimensions and shape to fit into the olfactory fissure
and to make an intimate interface with olfactory epithelium.
[0074] In an alternative embodiment, the drug transferring part of
the device has particular dimensions and shape to fit into the
olfactory fissure, whereas the remainder of the device which may
comprise a drug reservoir is positioned in the anterior or
posterior portion of the nasal cavity, or when the drug
transferring part is connected to a drug reservoir located outside
of the nasal cavity.
[0075] In another alternative embodiment, the device has particular
dimensions and shape not to obstruct the nasal airways.
Alternatively, the device contains air passage(s). Either
embodiment improves the subject's breathing function and
comfort.
[0076] It is very important to consider the anatomy of the
olfactory region of a mammal including human. The olfactory area is
quite different betIen primates and loIr animals. The anatomy of
the nasal passages is quite complex (human nasal cavity is
illustrated in FIG. 1). The olfactory fissure leading to the
cribriform plate at the roof of the nose is very narrow; ranging
from complete closure to 3-4 mm when a decongesting agent is used.
It is obvious that a drug-containing device in a liquid or
semi-liquid form will be preferred to enter such a difficult to
access region and to make an intimate contact with the olfactory
mucosa in every part of the olfactory region including the
olfactory fissure and the cribriform plate.
[0077] Thus, I disclose another preferred embodiment, where the
device comprises a drug dispersed in or linked to a gel-forming
polymer that can be either synthetic or natural. Therefor, the
pharmaceutical composition may exist in either liquid or solid
state, for example a liquid pharmaceutical composition with a
solidifying potential under certain conditions such as a change in
temperature. For example, the pharmaceutical composition is liquid
before administration but forms a gel when administered into the
nasal cavity and makes contact with the nasal mucosa which creates
particular conditions resulting in the pharmaceutical composition
to become solid or semi-solid. Such gel-forming conditions include
without limitation a particular pH preferably ranging from 6.0 to
8.5 and more preferred from 6.8 to 7.8, the body temperature in the
nasal cavity whereas the pharmaceutical composition is liquid when
the temperature is either higher or loIr than that in the nasal
cavity, but becomes a gel when administered into the nasal cavity.
In the preferred embodiment, the pharmaceutical composition is in a
solid state when the temperature is in the range from 35.0.degree.
C. to 38.5.degree. C., more preferred from 36.0.degree. C. to
38.0.degree. C., and most preferred from 36.4.degree. C. to
37.4.degree. C. (for examples of such liquid-gelling materials see
U.S. Pat. Nos. 4,478,822; 4,938,763; 5,384,333; 5,252,318;
4,188,373; 5,624,962; 5,599,534; 5,292,516; 5,306,501; 53,002,295
the disclosures of which are incorporated herein by reference in
their entirety).
[0078] It is also possible to modulate the temperature inside the
nasal cavity by an external temperature source, such as a heater of
a cooler (e.g. ice) applied externally to the nose or internally
into the nasal cavity, or as a stream of hot or cold air or fluid
in order to change the temperature of the pharmaceutical
composition and thus its solid or liquid state (depending on
whether it has to be administered or removed). Alternatively, the
pharmaceutical composition gradually solidifies into a gel upon
adding a solidifying agent which may be added immediately before or
after intranasal administration (for example, polyacrylamide
gradually solidifies upon addition of a combination of temed and
ammonium persulfate), or when exposed to the air upon transfer of
the composition from an air-protected environment into the nasal
cavity. Other mechanisms for making a liquid pharmaceutical
composition that solidifies in situ are obvious to those skilled in
the art, and include without limitation dissolving a non-reactive
polymer in biocompatible solvent to form a liquid, placing the
liquid into the olfactory region of the nasal cavity and allowing
the solvent to dissipate and to produce a solid or semi-solid drug
releasing device (for example see U.S. Pat. No. 4,938,763 the
disclosures of which are incorporated herein by reference in their
entirety). It is preferred that the polymer comprising the
pharmaceutical composition be biocompatible with the nasal mucosa.
Also, it is preferred that the polymer be biodegradable.
[0079] In the preferred embodiment, the pharmaceutical composition
provides long term or extended drug release, but may be a short
term one in particular when the release of the drug from the device
is controlled by additional physical or chemical means, including
without limitation ultrasound, electromagnetic energy including
electrotransport, light energy particularly lasers (which can be
applied with endoscopic assistance), ionizing radiation,
temperature, pH and/or osmolality changes, or others means known to
those skilled in the art. In the preferred embodiment, the
pharmaceutical composition provides continuous drug release.
HoIver, the release of the drug from the device may be pulsed or
intermittent in particular when the release is controlled by
additional physical or chemical means (see above).
[0080] In the preferred embodiment, (the material comprising) the
device has mucoadhesive properties, or is covered by a mucoadhesive
film on the contact surface. In another embodiment, the material
becomes mucoadhesive upon solidifying, or upon contacting the nasal
mucosa and/or hydrating.
[0081] The drug delivery system of the present invention may be
administered via syringe, catheter etc. to the olfactory region of
the nose. An example of method of administration is when the
subject is positioned so that the olfactory region is in the
gravity-dependent position, for example when the subject is supine
with hyperextended neck and with the foot end of bed elevated (FIG.
2). The drug delivery system in a liquid or semi-liquid form will
collect under gravity in the olfactory region filling the olfactory
fissure preferably up to the roof of the nose (cribriform plate),
and solidify later on (e.g. upon further exposure to body
temperature, or due to slowly acting solidifying agent, etc.). The
method of administration includes self-administration by the
subject or administration by a health professional preferably using
direct or indirect visual control, e.g., by an endoscope.
[0082] The drug transferring surface of the disclosed device
comprises a pharmaceutical composition-containing layer adapted to
provide an intimate interface with nasal mucosa in olfactory region
and to create an optimal drug transfer relationship. Examples of
materials suitable for the drug-transferring surface of the present
invention are multiple and are known to those skilled in the
art.
[0083] Alternatively, a liquid or semiliquid gel after it fills the
olfactory area of the nasal cavity is covered over by a
nonpermeable mucoadhesive film. The film adheres to the walls of
the nasal cavity around the area covered by the pharmaceutical
composition of the delivery system, thus securing an intimate
contact of the delivery system with the nasal mucosa of the
olfactory region and preventing the lateral spread of the
pharmaceutical composition to the non-olfactory mucosa.
[0084] In one embodiment, the mucoadhesive drug delivery device
comprises a drug reservoir and a mucoadhesive means. In an
alternative embodiment, a drug can be dispersed within the
mucoadhesive means. In yet another embodiment, a drug reservoir may
have mucoadhesive properties or become mucoadhesive upon contact
with nasal mucosa and/or hydration (e.g. a hydrogel).
[0085] Examples of the drug reservoir for the present invention
include, but not limited to, a hollow container such as a pouch or
cavity, a gel such as a hydrogel, microspheres, a porous sponge or
pad, a polymer preferably a polycationic polymer and most preferred
a chitosan or a chitosan salt or derivative, as Ill as reservoirs
similar to patches presently in use for the transdermal or
transmucosal drug deliver and known to those skilled in the
art.
[0086] The device disclosed in the present application may be
inserted as a double copy simultaneously in both nostrils. In
another embodiment, the device is inserted only in one nostril at a
time, which improves the subject's breathing function, and
increases the level of comfort. In the latter case, the device may
be alternatively inserted into either nostril, or always in the
same nostril that for some reason is preferred (better anatomical
access to the olfactory region e.g. due to a deviated septum).
[0087] Preferred means of physical enhancement of drug transport
through the nasal mucosa and/or other tissues in the nasal-CNS
pathway, or activation of drug transport from the device to the
nasal mucosa are electrical potential (including iontophoresis
and/or electroosmosis), ultrasound (including phonophoresis),
magnetic field, temperature or ionizing radiation.
[0088] Certain references are noted and incorporated herein by
reference as though set out at length herein: U.S. Pat. No.
5,298,017; U.S. Pat. No. 5,023,085; U.S. Pat. No. 5,624,898; U.S.
Pat. No. 3,989,816; U.S. Pat. No. 4,316,893; U.S. Pat. No.
4,405,616; U.S. Pat. No. 4,537,776; U.S. Pat. No. 4,557,934; U.S.
Pat. No. 5,744,166; Stoughton, Arch. Derm. v. 188, pp. 474-477
(1982); Cooper, J. Pharm. Sci., v. 73, pp. 1153-1156 (1984);
Akhtesi et al., J. Pharm. Pharmacol. v. 36, p 7P (1984); Olanoff,
et al. in Chapter 22 of Methods to Enhance Intranasal Peptide
Delivery in Controlled Release Technology Pharmaceutical
Application, ed. Ping I. Lee and William R. Good, pp. 301-309
(American Chemical Society, 1987).
[0089] The following items A-S recapitulate some of the scope and
details of the present inventions [claims pro se appear after item
S of this specification portion].
[0090] A. A method of delivering a pharmaceutical composition to
the nervous system of a mammal, comprising the steps of:
[0091] (a) administering said pharmaceutical composition
transnasally;
[0092] (b) enhancing delivery of said pharmaceutical composition
with a chemical permeation enhancer applied to the nasal
mucosa;
[0093] (c) enhancing delivery of said pharmaceutical composition
with phonophoresis; and,
[0094] (d) delivering said pharmaceutical composition to a target
site in the nervous system of the mammal via the nasal region.
[0095] B. The method as above at A wherein said chemical permeation
enhancer is selected from the group consisting of polycationic
polymers, chelators, long-chain acylcarnitines, calcium modulators,
cyclodextrins, bile salts, transdermal penetration enhancers,
lipophilic adjuvants, and mixtures thereof.
[0096] C. The method as above at A or B wherein said pharmaceutical
composition further comprises a solvent selected from the group
consisting of deionized water, an aqueous solvent and a non-aqueous
solvent such as DMSO or the like.
[0097] D. The method as above at any of A-C wherein said
pharmaceutical composition further comprises an additional agent,
said additional agent being an anesthetic agent.
[0098] E. The method as above at any of A-D wherein said
pharmaceutical composition further comprises an additional agent,
said additional agent being a decongestant.
[0099] F. The method as above at any of A-E wherein said
pharmaceutical composition further comprises an additional agent,
said additional agent being a vasoconstrictor.
[0100] G. The method as above at any of A-F wherein said
pharmaceutical composition further comprises an additional agent,
said additional agent being selected fro m the group consisting of
a decongestant, an anesthetic agent, a vasoconstrictor, and any
combination of said additional agents.
[0101] H. The method as above at any of A-G wherein said chemical
permeation enhancer is applied simultaneously with said
pharmaceutical composition.
[0102] I. The method as above at any of A-H wherein said chemical
permeation enhancer is applied, at least in part prior to
administration of said pharmaceutical composition to the transnasal
pathway.
[0103] J. A method of delivering a pharmaceutical composition to
the central nervous system of a mammal, comprising the steps
of:
[0104] (a) administering said pharmaceutical composition
transocularly;
[0105] (b) enhancing delivery of said pharmaceutical composition
with a chemical permeation enhancer applied to an ocular
surface;
[0106] (c) enhancing delivery of said pharmaceutical composition
with phonophoresis; and,
[0107] (d) delivering said pharmaceutical composition to a target
site of the nervous system of the mammal via the ocular region.
[0108] K. The method as above at J wherein said chemical permeation
enhancer is selected from the group consisting of polycationic
polymers, chelators, long-chain acylcarnitines, calcium modulators,
cyclodextrins, bile salts, transdermal penetration enhancers,
lipophilic adjuvants, and mixtures thereof.
[0109] M. The method as above at J or K wherein said pharmaceutical
composition further comprises a solvent selected from the group
consisting of deionized water, an aqueous solvent and a non-aqueous
solvent such as DMSO or the like.
[0110] N. The method as above at any of J-M wherein said
pharmaceutical composition further comprises an additional agent,
said additional agent being an anesthetic agent.
[0111] O. The method as above at any of J-N wherein said
pharmaceutical composition further comprises an additional agent,
said additional agent being a decongestant.
[0112] P. The method as above at any of J-O wherein said
pharmaceutical composition further comprises an additional agent,
said additional agent being a vasoconstrictor.
[0113] Q. The method as above at any of J-P wherein said
pharmaceutical composition further comprises an additional agent,
said additional agent being selected from the group consisting of a
decongestant, an anesthetic agent, a vasoconstrictor, and any
combination of said additional agents.
[0114] R. The method as above at any of J-Q wherein said chemical
permeation enhancer is applied simultaneously with said
pharmaceutical composition.
[0115] S. The method as above at any of J-R wherein said chemical
permeation enhancer is applied, at least in part prior to
administration of said pharmaceutical composition to the
transocular pathway.
* * * * *