U.S. patent application number 12/418917 was filed with the patent office on 2009-09-10 for controlled release delivery system for nasal application of neurotransmitters.
Invention is credited to Claudia Mattern.
Application Number | 20090227550 12/418917 |
Document ID | / |
Family ID | 38799348 |
Filed Date | 2009-09-10 |
United States Patent
Application |
20090227550 |
Kind Code |
A1 |
Mattern; Claudia |
September 10, 2009 |
CONTROLLED RELEASE DELIVERY SYSTEM FOR NASAL APPLICATION OF
NEUROTRANSMITTERS
Abstract
This invention relates to a galenical gel formulation for nasal
administration of neurotransmitters/neuromodulators such as
dopamine, serotonin or pregnenolone and progesterone. The special
lipophilic or partly lipophilic system of the invention leads to
high bioavailability of the active ingredient in plasma and brain
caused by sustained serum levels and/or direct or partly direct
transport from nose to the brain.
Inventors: |
Mattern; Claudia; (Stans,
CH) |
Correspondence
Address: |
FROMMER LAWRENCE & HAUG
745 FIFTH AVENUE- 10TH FL.
NEW YORK
NY
10151
US
|
Family ID: |
38799348 |
Appl. No.: |
12/418917 |
Filed: |
April 6, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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PCT/EP2007/008409 |
Sep 27, 2007 |
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12418917 |
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60828109 |
Oct 4, 2006 |
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Current U.S.
Class: |
514/171 ;
514/646 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 25/16 20180101; A61P 25/24 20180101; A61K 9/127 20130101; A61K
9/06 20130101; A61P 25/00 20180101; A61P 25/36 20180101; A61K
9/1605 20130101; A61K 9/0043 20130101; A61K 31/137 20130101; A61P
25/02 20180101; A61P 25/32 20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/171 ;
514/646 |
International
Class: |
A61K 31/56 20060101
A61K031/56; A61K 31/135 20060101 A61K031/135; A61P 25/00 20060101
A61P025/00 |
Claims
1. A formulation for nasal application comprising: (a) at least one
active ingredient selected from the groups consisting of a
neurotransmitter and a neuromodulator agent; (b) at least one
lipophilic or partly lipophilic carrier; (c) a compound or a
mixture of compounds having surface tension decreasing activity in
an amount effective for generating contact of the formulation with
a hydrophilic mucous membrane; and optionally (d) a
viscosity-regulating agent.
2. The formulation according to claim 1, wherein the at least one
active ingredient is a neurotransmitter selected from the group
consisting of acetylcholine, epinephrine, norepinephrine, dopamine,
serotonin, melatonin, histamine, glutamate, gamma aminobutyric
acid, aspartate, glycine, adenosine, ATP, GTP, Substance P,
N-acetylaspartylglutamate, Oxytocin, Vasopressin, Endorphin, zinc,
nitric oxide, carbon monoxide, and chemical modifications of such
molecules.
3. The formulation according to claim 2, wherein the
neurotransmitter is selected from the group consisting of dopamine,
serotonin, epinephrine and norepinephrin.
4. The formulation according to claim 3, wherein the
neurotransmitter is dopamine.
5. The formulation according to claim 1, wherein the at least one
active ingredient is a neuromodulator agent.
6. The formulation according to claim 5, wherein the neuromodulator
agent is a neurosteroid.
7. The formulation according to claim 6, wherein the neurosteroid
is selected from the group consisting of pregnenolone,
dehydroepiandrosterone, testosterone, dihydrotestosterone,
estradiol, progesterone, 3.alpha.-hydroxy-5.alpha.-pregnane-20-one,
metabolites of such molecules, and chemical modifications of such
molecules.
8. The formulation according to claim 6, wherein the neurosteroid
is pregnenolone.
9. The formulation according to claim 1, wherein the at least one
active ingredient is L-DOPA.
10. The formulation according to claim 1, wherein the active
ingredient is about 0.01% to about 6% by weight of the
formulation.
11. The formulation according to claim 1, wherein the active
ingredient is about 4% by weight of the formulation.
12. The formulation according to claim 1, wherein the at least one
lipophilic carrier or partly lipophilic carrier comprises an
oil.
13. The formulation according to claim 12, wherein the oil is a
vegetable oil.
14. The formulation according to claim 12, wherein the oil is
castor oil.
15. The formulation according to claim 1, wherein the amount of oil
is about 30% to about 95% by weight of the formulation.
16. The formulation according to claim 1, wherein the amount of oil
is about 90% by weight of the formulation.
17. The formulation according to claim 1, wherein component (c)
comprises at least one surfactant selected from the group
consisting of lecithin, fatty acid ester of polyvalent alcohols, of
sorbitanes, of polyoxyethylensorbitans, of polyoxyethylene, of
sucrose, of polyglycerol and/or at least one humectant selected
from the group consisting of sorbitol, glycerine polyethylene
glycol, and macrogol glycerol fatty acid ester, or a mixture
thereof.
18. The formulation according to claim 17, wherein component (c)
comprises an oleoyl macrogolglyceride or a mixture of oleoyl
macrogolglycerides.
19. The formulation according to claim 17, wherein component (c) is
about 1% to about 20% by weight of the formulation.
20. The formulation according to claim 17, wherein component (c) is
about 4% by weight of the formulation.
21. The formulation according to claim 1, further comprising a
viscosity-regulating agent.
22. The formulation according to claim 21, wherein the
viscosity-regulating agent comprises a thickener or gelling agent
selected from the group consisting of cellulose and cellulose
derivatives, polysaccharides, carbomers, polyvinyl alcohol,
povidone, colloidal silicon dioxide, cetyl alcohols, stearic acid,
beeswax, petrolatum, triglycerides and lanolin, or a mixture
thereof.
23. The formulation according to claim 22, wherein the
viscosity-regulating agent is colloidal silicon dioxide.
24. The formulation according to claim 21, wherein the
viscosity-regulating agent is about 0.5% to about 10% by weight of
the formulation.
25. The formulation according to claim 21, wherein the
viscosity-regulating agent is about 4% by weight of the
formulation.
26. A formulation for nasal application comprising: (a) dopamine or
L-DOPA in an amount of about 2% by weight; (b) castor oil in an
amount of about 90% by weight; (c) a compound or a mixture of
compounds comprising an oleoyl macrogolglyceride or a mixture of
oleoyl macroglyverides in an amount of about 4% by weight and
having surface tension decreasing activity in an amount effective
for generation of contact of the formulation with water; and
optionally (d) colloidal silicon dioxide in an amount of about 4%
by weight.
Description
INCORPORATION BY REFERENCE
[0001] This application is a continuation-in-part application of
International Patent Application Serial No. PCT/EP2007/008409 filed
27 Sep. 2007, which published as PCT Publication No. WO/2008/040488
on 10 Apr. 2008, which claims benefit of U.S. Provisional
Application No. 60/828,109 filed 4 Oct. 2006.
[0002] The foregoing application, and all documents cited therein
or during their prosecution ("appln cited documents") and all
documents cited or referenced in the appln cited documents, and all
documents cited or referenced herein ("herein cited documents"),
and all documents cited or referenced in herein cited documents,
together with any manufacturer's instructions, descriptions,
product specifications, and product sheets for any products
mentioned herein or in any document incorporated by reference
herein, are hereby incorporated herein by reference, and may be
employed in the practice of the invention.
FIELD OF THE INVENTION
[0003] The invention generally relates to a formulation used for
the controlled release and delivery of neurotransmitters and
neuromodulator agents to the systemic circulation and/or to brain
tissue via administration to the nasal cavity.
BACKGROUND OF THE INVENTION
[0004] A growing body of evidence suggests that brain-acting
compounds, such as neurosteroids (e.g., androgens, progestins) or
neurotransmitters (e.g., dopamine, derived from
3,4-dihydroxyphenylalanine (L-DOPA, or levodopa), serotonin,
epinephrin, norepinephrine), have a modulatory role in the
regulation of disorders influenced by receptors in the brain, such
as depression, Parkinson's disease, Alzheimer's, psychiatric
disorders and even loss of libido and aggression.
[0005] Neurosteroids act as modulators, either as stimulators or
inhibitors, of several neurotransmitters. Neurotransmitters are
chemicals that relay, amplify and modulate electrical signals
between a neuron and another cell. Some neurotransmitters are
excitatory, while others are primarily inhibitory. In many cases,
as with dopamine, it is the function of the receptor which
determines whether the transmitter is excitatory or inhibitory.
[0006] The brain floats in about 150 ml of cerebrospinal fluid
(CSF), which slowly circulates down through the four ventricles, up
through the subarachnoid space and exits into the cerebral veins
through the arachnoid vili. Since the brain has no lymphatic
system, the CSF serves as a partial substitute. While the brain and
CSF are separated by the somewhat permeable pia mater, the
blood-cerebrospinal fluid barrier and the blood-brain barrier (BBB)
represent substantial protection against undesirable blood
substances.
[0007] The BBB creates a protected chemical environment wherein
certain molecules are able to perform functions independent of the
functions those molecules may perform elsewhere in the body. One
example of such a molecule is the neurotransmitter dopamine. When
applied as an infusion, dopamine may be used for the treatment of
heart attacks or kidney failure, but this mode of administration of
dopamine is not suitable for the treatment of neurological
disorders, such as Parkinson's disease.
[0008] L-DOPA is typically used to increase dopamine levels in the
brain for the treatment of Parkinson's disease and Dopa-Responsive
deficiencies because it is able to cross the blood-brain barrier,
whereas dopamine itself cannot. Once L-DOPA has entered the central
nervous system (CNS), it is metabolized to dopamine by aromatic
L-amino acid decarboxylase.
[0009] Often, during treatment of neurological diseases such as
Parkinson's Disease, L-DOPA is administered to patients together
with other compounds, including carbidopa, benserazide, and
Entacapone/tolcapone. Further, other drugs or complimentary
therapies may be administered to Parkinson's patients in concert
with L-DOPA treatment, including dopamine agonists, MAO-B
inhibitors, glial-derived neurotropic factor for gene therapy, and
several neuroprotective agents.
[0010] To increase the efficacy of medicinal treatments of CNS
disorders, delivery of molecules to the brain via delivery to the
nasal cavity has been investigated. The inventors have recently
provided evidence in Banks, et al. (J Drug Target. 2009 February;
17(2):91-7), incorporated herein by reference, that intranasal
administration of testosterone is able to target the brain, and in
particular, is able to target the olfactory bulb, hypothalamus,
striatum, and hippocampus. Drug delivery to the brain via the nasal
cavity potentially offers many advantages that include direct
access to the brain, rapid adsorption into the nasal mucosa due to
the abundant presence of capillary vessels in the nose, rapid onset
of action, avoidance of hepatic first-pass metabolism, utility for
chronic medication, and ease of administration. However, still
little is known on factors controlling the nasal delivery of drugs
to the brain. A drug can reach the brain by different ways,
including olfactory neuronal pathway, extraneuronal olfactory
epithelial pathway, trigeminal nerve pathway, systemic pathway. It
is also possible that more of the aforementioned pathways may
contribute to the delivery of the molecule to the brain. Once a
drug is in the brain, it's amount can be further influenced by BBB
efflux transporter systems.
[0011] Thus, there has been a long-felt need in the art for
investigations into and the generation of formulations that
facilitate molecular uptake into the tissue of the nasal cavity,
thereby increasing the concentration of the drug in brain
tissue.
[0012] However, maintaining clinically effective drug
concentrations in vivo, particularly in brain tissue, has been a
challenge. The time period during which molecules may become
absorbed is reduced as a result of the rapid mucociliary clearance
of a therapeutic agent from the site of deposition and the presence
of enzymes in the nasal cavity, which that may cause degradation of
the therapeutic agent.
[0013] Many efforts have been made in the art in attempt to
overcome these limitations.
[0014] GB 1987000012176 relates to the use of bioadhesive
microspheres to increase the length of time that molecules reside
in the nasal cavity. It has also been found that the use of
enhancers and stabilizers improves permeability of the nasal
membrane and prevents drug degradation, respectively.
PCT/GB98/01147 (U.S. Pat. No. 6,432,440) pertains to the use of in
situ gelling pectin formulations for drug delivery.
[0015] Bayne, U.S. Reissue Patent No. RE29,892 pertains to a method
of increasing the dopamine concentration in brain tissue through
administration of a composition comprising dopamine and a hydrazine
compound. The method allows for administration of the composition
topically, rectally, orally, or parenterally. Preferred
compositions include hydrazine compounds such as
L-.alpha.-hydrazino-.alpha.-lower alkyl-3,4-dihydroxyphenyl
propionic acid and L-DOPA and its pharmaceutically accepted
salts.
[0016] Haffner et al., U.S. Pat. No. 4,826,852, relates to the
treatment of psychoses such as schizophrenia and discloses methods
of administrating ergolinyl compounds to increase dopamine
concentrations in mammalian brain tissue.
[0017] Additionally, Wenzel et al., U.S. Pat. No. 5,624,960,
pertains to the treatment of Parkinson's disease through the oral
administration of a composition containing levodopa and carbidopa
(MK-486). Further, Mandel et al., U.S. Pat. No. 6,319,905, relates
to the tightly modulated production of L-DOPA in the mammalian
brain by gene therapy. In Mendel et al., modulators such as
tetrahydropterin (PH4) are used to control the generation of
dopamine.
[0018] Despite the latter attempts to develop an effective nasal
delivery system, there remains a need in the art to identify a
formulation that, inter alia, limits the rate of mucociliary
clearance and degradation of molecules in the nasal cavity, thereby
increasing the brain's availability to such molecules, particularly
neurotransmitters. Preferably, the formulation should have physical
and chemical properties that facilitates brain uptake of
molecules/drugs, such as dopamine. The identification of a
formulation that may increase the bioavailability of
neurotransmitters to brain tissue would provide much-needed
treatment options for diseases associated with, for example,
dopamine or serotonin deficiency in the brain, including
depression, Parkinson's disease, attention deficit hyperactivity
disorder (ADHD), addiction to drugs and alcohol, and various
psychiatric disorders.
[0019] Citation or identification of any document in this
application is not an admission that such document is available as
prior art to the present invention.
SUMMARY OF THE INVENTION
[0020] The presently claimed invention demonstrates that the
incorporation of various neurotransmitter agents into a unique
lipophilic or partly lipophilic formulation, which when delivered
to the nasal cavity, results in clinically effective sustained
serum levels in plasma and CSF. These levels in turn increase the
bioavailability of drugs to the systemic circulation and to brain
tissue.
[0021] The presently claimed invention comprises a formulation for
nasal application comprising: (a) at least one active ingredient
selected from the groups consisting of a neurotransmitter and a
neuromodulator agent; (b) at least one lipophilic or partly
lipophilic carrier; and (c) a compound or a mixture of compounds
having surface tension decreasing activity, an amount effective for
generation of contact of the formulation with a hydrophilic mucous
membrane and optionally (d) a viscosity-regulating agent. The
formulation may also contain minor proportions of one or more
compounds including but not limited to absorption promoters,
substances that inhibit enzymatic degradation or efflux,
preservatives, flavors and antioxidants.
[0022] In one embodiment of the invention, the at least one active
ingredient is a neurotransmitter. In a preferred embodiment, the
neurotransmitter may be dopamine, serotonin, epinephrine or
norepinephrine.
[0023] In another embodiment, the at least one active ingredient is
a neurotransmitter or neuromodulator agent(s).
[0024] In yet another embodiment, the formulation may comprise more
than one neurotransmitter and/or neuromodulator agent. In a
preferred embodiment, the formulation may comprise dopamine or
L-DOPA and their derivatives.
[0025] In one embodiment, the active ingredient(s) may comprise
0.01 to 6% by weight, preferably 0.1 to 4% by weight, more
preferably 0.5 to 2% by weight, and most preferably at around 2% by
weight of the formulation.
[0026] In one embodiment of the invention, the lipophilic carrier
may comprise oil, fats and/or other lipids. Lipids may be any
lipophilic molecules, including but not limited to fats, oils,
waxes, cholesterol, sterols, monoglycerides, diglycerides,
phospholipids.
[0027] In a preferred embodiment, the oil is a vegetable oil. Most
preferably, the oil is caster oil.
[0028] In yet another preferred embodiment, the oil may between 30%
and 98% by weight, preferably between 60 and 98% by weight, more
preferably between 75% and 95% by weight, even more preferably
between 85% and 95% by weight and most preferably around 90% by
weight of the formulation.
[0029] In a further embodiment, component (c) may comprise at least
one surfactant selected from the group consisting of lecithin,
fatty acid ester of polyvalent alcohols, of sorbitanes, of
polyoxyethylensorbitans, of polyoxyethylene, of sucrose, of
polyglycerol and/or at least one humectant selected from the group
consisting of sorbitol, glycerine, polyethylene glycol, and
macrogol glycerol fatty acid ester, or a mixture thereof. In a
preferred embodiment, component (c) may comprise an oleoyl
macrogolglyceride or a mixture of oleoyl macrogolglycerides.
[0030] In a preferred embodiment, component (c) may comprise 1 to
20% by weight, preferably 1 to 10% by weight, more preferably 1 to
5% by weight, and most preferably at around 4% by weight of the
formulation.
[0031] In another embodiment, the viscosity-regulating agent may
comprise a thickener or gelling agent selected from the group
consisting of cellulose and cellulose derivatives, polysaccharides,
carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide,
cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides
and lanolin, or a mixture thereof. More preferably, the
viscosity-regulating agent is colloidal silicon dioxide.
[0032] In a preferred embodiment, the viscosity-regulating agent
may comprise 0.5 to 10% by weight, preferably 0.5 to 5% by weight,
more preferably 2 to 5% by weight, and most preferably at around 4%
by weight of the formulation.
[0033] While not wishing to be bound by theory, it is believed that
nasal administration of the galenical gel formulation of the
presently claimed invention may be able to facilitate selective
recruitment of molecules to brain tissue by providing access
directly to the brain, which in turn may provide for new clinical
applications, for example, the use of neurotransmitters to treat
CNS disorders.
[0034] Accordingly, it is an object of the invention to not
encompass within the invention any previously known product,
process of making the product, or method of using the product such
that Applicant reserves the right and hereby disclose a disclaimer
of any previously known product, process, or method. It is further
noted that the invention does not intend to encompass within the
scope of the invention any product, process, or making of the
product or method of using the product, which does not meet the
written description and enablement requirements of the USPTO (35
U.S.C. .sctn. 112, first paragraph) or the EPO (Article 83 of the
EPC), such that Applicant reserves the right and hereby disclose a
disclaimer of any previously described product, process of making
the product, or method of using the product.
[0035] It is noted that in this disclosure and particularly in the
claims and/or paragraphs, terms such as "comprises", "comprised",
"comprising" and the like can have the meaning attributed to it in
U.S. patent law; e.g., they can mean "includes", "included",
"including", and the like; and that terms such as "consisting
essentially of" and "consists essentially of" have the meaning
ascribed to them in U.S. patent law, e.g., they allow for elements
not explicitly recited, but exclude elements that are found in the
prior art or that affect a basic or novel characteristic of the
invention.
[0036] These and other embodiments are disclosed or are obvious
from and encompassed by, the following Detailed Description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] The following detailed description, given by way of example,
but not intended to limit the invention solely to the specific
embodiments described, may best be understood in conjunction with
the accompanying drawings, in which:
[0038] FIG. 1 shows the effect of nasal dopamine gel on immobility
and climbing of depressed rats.
[0039] FIG. 2 shows the concentration of dopamine and metabolites
in nucleus accumbens and neostriatum after nasal administration of
dopamine.
DETAILED DESCRIPTION
[0040] The galenical gel formulation of the presently claimed
invention is chemically and physically stable and can be in the
form of a suspension or a solution of the pharmacologically active
substance. In a preferred embodiment, the galenical gel formulation
of the invention is filled into a preservative-free device able to
accurately deliver doses of the above formulation, even at a high
viscosity.
[0041] After nasal application of the galenical gel formulation,
the active ingredient or active ingredient particles are typically
efficiently trapped at the deposition site and are typically
absorbed at a predictable rate across the mucous membrane of the
patient, thereby limiting possible deactivation by metabolizing
enzymes and/or protein-binding.
[0042] It is also understood that the terms and expressions used
herein have the ordinary meaning as is accorded to such terms and
expressions with respect to their corresponding respective areas of
inquiry and study except where specific meanings have otherwise
been set forth herein.
[0043] The term "higher availability" or "higher bioavailability"
shall mean that after application of the active ingredient(s),
significant and constant in vivo therapeutic drug concentrations,
especially in the brain, are maintained for an extended period of
time.
[0044] The composition of the invention may comprise a
neurotransmitter and/or neuromodulator agent. A neurotransmitter,
as used herein, may be a molecule used for signaling between nerve
cells or neurons. Neurotransmitter molecules typically pass between
neurons at synapses, and may causes a rapid, short-lived and
dramatic response. Neurotransmitters may degrade rapidly, resulting
in restoration of the resting membrane potential. Examples include
but are not limited to Acetylcholine, Monoamines (epinephrine,
norepinephrine, dopamine, serotonin, melatonin, histamine), Amino
acids (glutamate, gamma aminobutyric acid (GABA), aspartate,
glycine), Purines (Adenosine, ATP, GTP, and their derivatives),
neuroactive peptides (Substance P, N-Acetylaspartylglutamate),
Neurohypophyseal transmitters (Oxytocin, Vasopressin), Opioids
(Endorphin), zinc, nitric oxide, carbon monoxide, and chemical
modifications of such molecules, such as esters.
[0045] Neurotransmitters such as dopamine, serotonin, epinephrine
and norepinephrine contain the catechol moiety typically
synthesized from the amino acid tyrosine.
[0046] One neurotransmitter commonly associated with any number of
responses is dopamine or 4-(2-aminoethyl)-1,2-benzenediol. Dopamine
is commonly regarded as an endogenous catecholamine with .alpha.
and .beta. adrenergic activity.
[0047] L-DOPA is commonly synthesized from aminotyramine and
converted into dopamine in the brain. Other neurotransmitters are
typically contained in synaptic vesicles in terminals of the
presynaptic neuron, and upon stimulation of an action potential,
are released into the synaptic cleft to induce a response in the
post synaptic cell. Iontophoresis of the neurotransmitter into a
synaptic cleft induces the same postsynaptic response. The
neurotransmitter then degrades rapidly resulting in restoration of
the resting potential.
[0048] Other catecholamines known to have various utilities include
epinephrine, norepinephrine, and serotonin.
[0049] A neuromodulator agent, as used herein, may be a substance
other than a neurotransmitter, released by a neuron at a synapse
and conveying information to adjacent or distant neurons, either
enhancing or dampening their activities. Neuromodulation is the
process in which several classes of neurotransmitters in the
nervous system regulate diverse populations of neurons.
Neuromodulators may act not only on the input system but may change
the transformation itself to produce the proper contractions of
muscles as output. Neuromodulator agents may also include
neurosteroids. A variety of steroids are synthesized in the central
and peripheral nervous system, especially in myelinating glial
cells, from cholesterol or steroidal precursors imported from
peripheral sources. Such steroids are defined as neurosteroids.
Neurosteroids may rapidly alter neuronal excitability through
interaction with neurotransmitter-gated ion channels. In addition,
neurosteroids may also exert effects on gene expression via
intracellular steroid hormone receptors. Examples include but are
not limited to pregnenolone, dehydroepiandrosterone, their
sulfates, and reduced metabolites such as the tetrahydroderivative
of progesterone 3.alpha.-hydroxy-5.alpha.-pregnane-20-one.
Neuromodulator agents also include chemical modifications of
neurosteroids, such as esters and synthetic neurosteroids such as
minaxolone, ganaxolone.
[0050] In a preferred embodiment, the active ingredient may
comprise 0.01 to 6% by weight, preferably 0.1 to 4% by weight, more
preferably 0.5 to 2% by weight, and most preferably at around 2% by
weight of the formulation.
[0051] The carrier of the invention functions to dissolve or
suspend the drug and otherwise support the various constituents of
the invention. To that end, the carrier has a lipophilic nature or
character. Suitable families of oils include fatty acids and oils
such as mineral and vegetable oils, in particular, fatty acids and
oils derived from vegetable stock are especially useful. Both
linear and branched chain acids and oils are useful including those
oils and acids with various levels of saturation and substitution.
Chain size including but is not limited to formic, acetic,
propionic, butyric, valeric, caproic, emanthic, caprylic,
pelargonic, capric, laurie, myristic, palmitic and stearic, among
others, all represent useful oil and acid moieties.
[0052] The term "lipophilic carrier" may comprise, but is not
limited to, fats and/or vegetable oil such as castor oil, soybean
oil, sesame oil, or peanut oil, fatty acid esters such as ethyl-
and oleyloleat, isopropylmyristate, medium chain triglycerides,
glycerol esters of fatty acids, or polyethylene glycol,
phospholipids, white soft paraffin, or hydrogenated castor oil, or
a mixture thereof. In one embodiment, the active ingredient may
also be incorporated into an oil mixture. In a preferred
embodiment, the vegetable oil is castor oil.
[0053] The particular amount of lipophilic carrier that constitutes
an effective amount is dependent on the particular viscosity
regulating agent used in the formulation. It is therefore not
practical to enumerate specific amounts for use with specific
formulations of the invention.
[0054] In a preferred embodiment, the lipophilic carrier may
comprise between 30% and 98% by weight, preferably between 60 and
98% by weight, more preferably between 75% and 95% by weight, even
more preferably between 85% and 95% by weight, and most preferably
around 90% by weight of the formulation.
[0055] The surface active agent or surfactant of the invention
functions to decrease surface tension in the composition of the
invention. Surfactants are generally regarded as those compositions
which have both hydrophilic and lypophilic character. The
lypophilic character of the surfactant typically takes the form of
a pendent moiety having little if any charge. In turn, the
hydrophilic character of the surfactant is typically charged and
dictates the class into which the surfactant is identified. For
example, surfactants typically used in the invention include
nonionic surfactants, anionic surfactants, amphoteric surfactants,
and cationic surfactants.
[0056] In one embodiment, component (c), a compound or a mixture of
compounds having surface tension decreasing activity, may comprise
at least a surfactant including, but not limited to, lecithin,
fatty acid ester of polyvalent alcohols, fatty acid ester of
sorbitanes, fatty acid ester of polyoxyethylensorbitans, fatty acid
ester of polyoxyethylene, fatty acid ester of sucrose, fatty acid
ester of polyglycerol, and/or at least one humectant such as
sorbitol, glycerine, polyethylene glycol, or macrogol glycerol
fatty acid ester. Particularly useful, however, are oleoyl
macrogolglycerides (such as LABRAFIL.RTM. M 1944 CS, as available
from Gattefosse (Saint-Priest, France)).
[0057] As defined herein, "surface tension decreasing activity"
shall mean having a surface tension that results in generating
contact of the formulation to the hydrophilic mucous membranes of
the nasal cavity.
[0058] In one embodiment, the active ingredient/neurotransmitter
may be incorporated into a surfactant mixture. The particular
amount of surfactant that constitutes an effective amount is
dependent on the particular oil or oil mixture used in the
formulation. It is therefore not practical to enumerate specific
amounts for use with specific formulations of the invention.
Typically, however, the surfactant may comprise 1 to 20% by weight,
preferably 1 to 10% by weight, more preferably 1 to 5% by weight,
and most preferably at around 4% by weight of the formulation.
[0059] The term "viscosity-regulating agent" shall mean a thickener
or gelling agent.
[0060] Examples of a viscosity-regulating agent include, but are
not limited to, cellulose and derivatives thereof, polysaccharides,
carbomers, polyvinyl alcohol, povidone, colloidal silicon dioxide,
cetyl alcohols, stearic acid, beeswax, petrolatum, triglycerides,
lanolin, or the like. A preferred viscosity regulating agent is
colloidal silicon dioxide (such as AEROSIL.RTM., as available from
Degussa).
[0061] The incorporation of the active ingredient is also possible
into a mixture of thickeners or gelling agents. The particular
amount of thickener/gelling agent that constitutes an effective
amount is dependent on the particular oil or oil mixture used in
the formulation. It is therefore not practical to enumerate
specific amounts for use with specific formulations of the
invention. Typically, however, the thickener/gelling agent(s) may
comprise 0.5 to 10% by weight, preferably 0.5 to 5% by weight, more
preferably 2 to 5% by weight, and most preferably at around 4% by
weight of the formulation.
[0062] Preferred weight percentages for components of the galenical
gel formulation are shown in Table 1.
TABLE-US-00001 TABLE 1 Preferred weight percentages components of
the galenical gel formulation Wt-% Useful Preferred More Preferred
Active Ingredient 0.01 to 6 2 to 4 0.5 to 2 (e.g. Neurotransmitter/
Neuromodulator agent Lipophilic Carrier 30 to 98 60 to 98 85 to 95
Surfactant 1 to 20 1 to 10 1 to 5 Viscosity Regulating 0.5 to 10
0.5 to 5 2 to 5 Agent
[0063] Generally, the galenical formulation of the invention can be
prepared easily by the following conventional method:
[0064] The lipophilic carrier and surfactant are filled into a
stirrer vessel and about 75% of the viscosity regulating agent is
mixed in. The active ingredient is added while stirring to obtain a
homogenous dispersion of the active ingredient. Next, the
formulation is adjusted to the necessary viscosity with the
remainder of the viscosity regulating agent.
[0065] In a preferred embodiment, the formulation may be filled
into a preservative-free container.
[0066] Because the active ingredient, particularly a
neurotransmitter, may have lower levels of solubility in water,
release from the formulation is the rate-limiting step for
adsorption. The presently claimed invention demonstrates that the
incorporation of the active ingredient into an oily formulation
containing a suitable surfactant leads to physiologically
clinically effective serum and brain levels and to an appropriate
sustained action of the active ingredient over time.
[0067] This sustained and clinically favorable release of the
active ingredient is due to the interaction of the compounds in the
oily carrier, which remains on the mucous membrane of the nasal
cavity for a prolonged duration of time.
[0068] The active ingredient of this invention may be introduced
into the formulation also in a processed form, such as
microspheres, liposomes, among others.
[0069] The formulation according to this invention may also be
processed into powder form, such as by lyophilization or
spray-drying.
[0070] The most preferred formulation of the presently claimed
invention is presented in Table 2.
TABLE-US-00002 TABLE 2 Most Preferred formulation Compound Amount
per container Delivery per spray Dopamine/L-DOPA 2% ~2.8 mg
Colloidal silicon dioxide 4% ~4.2 mg Oleoyl macrogol-glycerides 4%
~5.6 mg Castor Oil 90% ~127.4 mg
[0071] In one embodiment, the formulation is administered to a
patient. In a preferred embodiment, the formulation is administered
to a human.
[0072] When administered to a patient, the formulation that
optionally comprises a pharmaceutically acceptable vehicle may be
administered by absorption through mucocutaneous linings and may be
administered together with another biologically active agent.
Administration may be local.
[0073] In a specific embodiment, the term "pharmaceutically
acceptable" means approved by a regulatory agency of the Federal or
a state government or listed in the U.S. Pharmacopeia or other
generally recognized pharmacopeia or otherwise proven as safe for
use in animals, mammals, and more particularly in humans. The term
"vehicle" refers to a diluent, adjuvant, excipient, or carrier with
which a compound of the invention is administered. Such
pharmaceutical vehicles can be lipophilic semisolids or liquids
such as oils, including those of petroleum, animal, vegetable or
synthetic origin, such as peanut oil, soybean oil, mineral oil,
sesame oil and the like.
[0074] The amount of the formulation that will be effective in the
treatment of a particular disease will depend on the nature of the
disease, and can be determined by standard clinical techniques. In
addition, in vitro or in vivo assays may optionally be employed to
help identify optimal dosage ranges. The precise dose to be
employed will also depend on the seriousness of the disease, and
should be decided according to the judgment of the practitioner and
each patient's circumstances.
[0075] Recommended dosages for administration by inhalation are in
the range of about 0.001 milligram to about 200 milligrams per
kilogram of body weight per day. Effective doses may be
extrapolated from dose-response curves derived from in vitro or
animal model test systems. Such animal models and systems are well
known in the art.
[0076] The formulation is preferably assayed in vitro and in vivo,
for the desired therapeutic or prophylactic activity, prior to use
in humans. Animal model systems can be used to demonstrate safety
and efficacy.
EXAMPLES
[0077] The invention will now be further described by way of the
following non-limiting examples.
Example 1
Nasal Administration of Dopamine to Rats
[0078] A dopamine (DA) gel of the inventive formulation was nasally
administered to rats used in the validated "forced swimming test."
As shown in FIG. 1, the administration of dopamine results in
anti-depressive-like effects. As shown in FIG. 2, strong
dopaminergic activity in the neostriatum and ventral striatum
(nucleus accumbens) was observed after nasal application of
dopamine with the inventive formulation.
[0079] Generally, antidepressants must be administered for an
extended length of time before antidepressive effects are observed.
Surprisingly, after nasal application to rat of the dopamine gel
formulation, antidepressive effects occurred within hours and
without any observable side effects, such as those side effects
known to occur with desipramine (apathy) or fluoxetine (weight
loss).
[0080] After nasal application to rats of dopamine in the inventive
gel formulation, the concentration of dopamine in the nucleus
accumbens and neostriatum level increased rapidly by more than 1000
percent. These results differ from those previously described.
After nasal application of an aqueous dopamine solution to mice,
Bjorn Jansson, Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Pharmacy 305 (2004), found dopamine in the
olfactory bulb but the compound peaked after four hours. After
nasal application to rats of aqueous dopamine solution, Maria
Dahlin, Comprehensive Summaries of Uppsala Dissertations from the
Faculty of Pharmacy 240 (2000), found dopamine in CSF after a short
time but the increase of the compound from baseline was much lower
than with the nasal gel of the invention. Ikeda et al., Chem.
Pharm. Bull. 40(8): 2155-2158 (1992), increased bioavailability of
nasally-given dopamine by some degree using the excipients
hydroxypropyl cellulose (HPC) and Azone
(1-dodecylazacycloheptan-2-one), respectively. De Souza Silva et
al., Synapse 27:294-302 (1997), showed that by nasally applying to
rats an aqueous L-DOPA methyl ester solution (50 mg/kg), the
dopamine level in the neostriatum were increased by about 130%. The
metabolites 3,4-dihydroxyphenyl acetic acid (DOPAC) and
homovanillic acid (HVA) slightly increased by contrast to what was
seen after intraperitoneal (IP) application of L-DOPA methyl ester
in De Souza Silva et al., J. Neurochem. 68(1): 233-239 (1997).
[0081] Furthermore, the metabolism of dopamine appears to be quite
different than that previously described. Unexpectedly, as shown in
FIG. 2, dopamine in the CSF was not metabolized to
3,4-dihydroxyphenyl acetic acid (DOPAC) or homovanillic acid (HVA)
as is typically seen. These results demonstrate that nasal
application of dopamine in the inventive gel formulation may be
useful for the treatment of diseases associated with dopamine
deficiency in the brain, such as Parkinson's disease, attention
deficit hyperactivity disorder (ADHD), and addiction to drugs
and/or alcohol.
[0082] The features disclosed in the foregoing description, in the
claims and/or in the drawings may, both separately and in any
combination thereof, be material for realizing the invention in
diverse forms thereof.
[0083] Having thus described in detail preferred embodiments of the
present invention, it is to be understood that the invention
defined by the above paragraphs is not to be limited to particular
details set forth in the above description as many apparent
variations thereof are possible without departing from the spirit
or scope of the present invention.
* * * * *