U.S. patent application number 16/570156 was filed with the patent office on 2020-01-23 for pharmaceutical composition comprising betahistine.
The applicant listed for this patent is Otolanum AG. Invention is credited to Thomas MEYER, Christopher John WRAIGHT.
Application Number | 20200022963 16/570156 |
Document ID | / |
Family ID | 61187302 |
Filed Date | 2020-01-23 |
United States Patent
Application |
20200022963 |
Kind Code |
A1 |
WRAIGHT; Christopher John ;
et al. |
January 23, 2020 |
PHARMACEUTICAL COMPOSITION COMPRISING BETAHISTINE
Abstract
The present disclosure relates to a pharmaceutical composition
comprising as active substance betahistine or a pharmaceutically
acceptable salt thereof, for use in the treatment of otological or
neurological disorders in a human subject by intranasal
application.
Inventors: |
WRAIGHT; Christopher John;
(Blackburn, AU) ; MEYER; Thomas; (Zuchwil,
CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Otolanum AG |
Zug |
|
CH |
|
|
Family ID: |
61187302 |
Appl. No.: |
16/570156 |
Filed: |
September 13, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15887388 |
Feb 2, 2018 |
10456386 |
|
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16570156 |
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62453931 |
Feb 2, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/10 20130101;
A61K 45/06 20130101; A61K 9/0043 20130101; A61K 47/32 20130101;
A61K 9/08 20130101; A61K 47/26 20130101; A61K 47/38 20130101; A61P
27/16 20180101; A61K 9/0073 20130101; A61K 31/4402 20130101 |
International
Class: |
A61K 31/4402 20060101
A61K031/4402; A61K 45/06 20060101 A61K045/06; A61K 47/10 20060101
A61K047/10; A61K 47/26 20060101 A61K047/26; A61P 27/16 20060101
A61P027/16; A61K 47/38 20060101 A61K047/38; A61K 9/00 20060101
A61K009/00; A61K 47/32 20060101 A61K047/32 |
Claims
1-59. (canceled)
60. A pharmaceutical composition for intranasal delivery to a human
patient, comprising a solution or suspension of therapeutically
effective amount of betahistine dihydrochloride and hydroxypropyl
methylcellulose as a viscosity enhancing agent.
61. The pharmaceutical composition of claim 60, wherein after a
single intranasal administration to a human, the C.sub.max of
betahistine ranges from 80-125% of about 3000 pg/mL for a 5 mg
betahistine dihydrochloride dose.
62. The pharmaceutical composition of claim 60, wherein after a
single intranasal administration to a human, the C.sub.max of
betahistine ranges from 80-125% of about 8000 pg/mL for a 10 mg
betahistine dihydrochloride dose.
63. The pharmaceutical composition of claim 60, wherein after a
single intranasal administration to a human, the AUC.sub.0-last of
betahistine ranges from about 80%-125% of about 1300 pg*hr/mL for a
5 mg betahistine dihydrochloride dose.
64. The pharmaceutical composition of claim 60, wherein after a
single intranasal administration to a human, the AUC.sub.0-last of
betahistine ranges from about 80%-125% of about 3000 pg*hr/mL for a
20 mg betahistine dihydrochloride dose.
65. The pharmaceutical composition of claim 60, wherein the
t.sub.max of betahistine in human plasma after single intranasal
dose of the composition is about 0.08 h or greater.
66. The pharmaceutical composition of claim 60, further comprising
one or more moisturizing agent.
67. The pharmaceutical composition of claim 60, wherein the one or
more moisturizing agent is selected from the group consisting of
glycerin, ethylene glycol, propylene glycol, propylene glycol 400,
hexalene glycol, butylene glycol, dextrose, glyceryl triacetate,
polydextrose, glycerol, glyceryl triacetate, sorbitol, mannitol,
and combinations thereof.
68. The pharmaceutical composition of claim 67, wherein the one or
more moisturizing agent is selected from the group consisting of
glycerin, polyethylene glycol 400 and propylene glycol.
69. The pharmaceutical composition of claim 60, wherein the
composition is in the form of a unit dose comprising the
betahistine dihydrochloride in an amount of about 5 mg, about 10
mg, about 20 mg, about 40 mg, or about 80 mg.
70. The pharmaceutical composition of claim 60, wherein the
C.sub.max of betahistine in human plasma after a single intranasal
dose of the composition is at least about 3 ng/mL.
71. The pharmaceutical composition of claim 70, wherein the single
intranasal dose of the composition comprises about 5 mg, about 10
mg, about 20 mg, or about 40 mg of betahistine dihydrochloride.
72. The pharmaceutical composition of claim 60, wherein the
AUC.sub.0-last of betahistine in human plasma after a single
intranasal dose of the composition is at least about 1200
hr*pg/mL.
73. The pharmaceutical composition of claim 72, wherein the single
intranasal dose of the composition comprises about 5 mg, about 10
mg, about 20 mg, or about 40 mg of betahistine dihydrochloride.
74. The pharmaceutical composition of claim 60, further comprising
at least one enzyme inhibitor or absorption promoter.
75. The pharmaceutical composition of claim 60, wherein the pH of
the composition is about 4.4 to about 6.4.
76. The pharmaceutical composition of claim 1, wherein the
viscosity of the composition is about 1 cps to about 10 cps as
measured by the USP <911> Viscosity method.
77. A method of treating an inner ear disorder, vestibular
disorder, neurotological disorder, otological disorder,
neurological disorder, obesity, weight gain, or eating disorders in
a subject in need thereof, comprising intranasally administering
the pharmaceutical composition of claim 60 to the subject.
78. The method of claim 77, wherein the method is for treating a
vestibular disorder.
79. The method of claim 78, wherein the vestibular disorder is
vestibular vertigo or Meniere's disease.
80. The method of claim 77, wherein the method is for treating an
inner ear disorder selected from tinnitus or hearing loss.
81. The method of claim 77, wherein the method is for treating
weight gain, wherein the weight gain is induced by administration
of antipsychotic drugs acting on histamine receptors.
82. The method of claim 81, wherein the antipsychotic drug is
olanzapine.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of U.S.
application Ser. No. 15/887,388, filed on Feb. 2, 2018, which
claims the benefit of priority to U.S. Provisional Application No.
62/453,931 filed on Feb. 2, 2017, the contents of each of which are
hereby incorporated by reference in their entirety.
FIELD
[0002] The present disclosure generally relates to pharmaceutical
compositions comprising betahistine or a pharmaceutically
acceptable salt thereof, and methods of use thereof, for example,
in the treatment of otological or neurological disorders.
BACKGROUND
[0003] Medicinal agents useful in the treatment of vestibular
disorders or relieving symptoms of vestibular disorders, such as
histamine, are known to act via the histaminergic system. Histamine
is a potent bioactive substance that has been studied for nearly a
century, acting as an aminergic neurotransmitter in the nervous
system and as a local mediator in the gut, skin, and immune system
peripherally and in the brain. Betahistine is a structural analog
of histamine with similar pharmacologic properties, but without
potentially severe side effects of histamine such as anaphylactic
reactions.
[0004] Betahistine is known to have therapeutic benefits in the
treatment of vestibular vertigo, e.g. in benign paroxysmal
positional vertigo, vestibular neuritis, or Meniere's disease. The
therapeutic effects of betahistine in Meniere's disease, a
condition characterized by vertigo, tinnitus, hearing loss and the
sensation of pressure or pain in the affected ear, have been
evaluated in a large number of clinical trials. However, the
results of the trials are controversial and the general opinion of
the reviewers is that there is still insufficient evidence to say
whether betahistine has any effect on Meniere's disease or not.
Betahistine is also known to have therapeutic benefits in
vestibular rehabilitation, e.g., significantly shortened time to
recovery for postural stability and subjective visual vertical and
head orientation in Meniere's patients following vestibular
neurectomy.
[0005] Betahistine is also known to have therapeutic effects in the
treatment of neurological disorders such as obesity, attention
deficit hyperactivity disorder, cerebrovascular disease/dementia,
narcolepsy/sleep disorders, Parkinson, addiction, schizophrenia,
Gilles de la Tourette syndrome, or Alzheimer's disease.
[0006] In humans, betahistine is usually administered orally in the
form of tablets or a solution, usually two to three times daily, up
to 6 times a day. Betahistine is known for its short plasma
half-life (3-4 h) which necessitates frequent administration and
may lead to noncompliance, especially in elderly patients. In
addition, after oral administration, betahistine is readily and
almost completely absorbed from all parts of the gastro-intestinal
tract. Following absorption, the drug is rapidly and almost
completely metabolized into 2-pyridylacetic acid (2-PAA; which has
no pharmacological activity) by monoamine oxidase. Due to its very
high first pass metabolism, the absolute bioavailability of orally
administered betahistine is estimated to be around 1% (SmPC).
Accordingly, plasma levels of betahistine are very low.
[0007] Thus, the strong first-past effect following oral
administration of betahistine limits the compound's efficacy in
clinical practice, and substantially higher doses may indeed be
necessary in order to achieve more pronounced results. Therefore,
there is a need to provide improved pharmaceutical compositions
comprising betahistine, and methods of administration thereof for
the treatment of otological or neurological disorders, including
inner ear dysfunctions, which provides increased efficacy and
allows for a reduced frequency and/or daily dosage, as well as to
attain a more rapid and prolonged effect.
SUMMARY OF THE DISCLOSURE
[0008] In various embodiments, the present disclosure is directed
to pharmaceutical compositions for intranasal delivery to a human
patient, comprising a solution or suspension of therapeutically
effective amount of betahistine or a pharmaceutically acceptable
salt thereof and a viscosity enhancing agent.
[0009] In particular embodiments, the present disclosure is
directed to pharmaceutical compositions as described herein,
wherein after a single intranasal administration to a human, the
C.sub.max ranges from 80-125% of: about 640 pg/mL for a 5 mg
betahistine dose; about 2000 pg/mL for a 10 mg betahistine dose;
about 4000 pg/mL for a 20 mg betahistine dose; or about 10500 pg/mL
for a 40 mg betahistine dose.
[0010] In particular embodiments, the present disclosure is
directed to pharmaceutical compositions as described herein,
wherein after a single intranasal administration to a human, the
AUC.sub.0-last ranges from about 80%-125% of: about 210 pg*hr/mL
for a 5 mg betahistine dose; about 500 pg*hr/mL for a 10 mg
betahistine dose; about 1600 pg*hr/mL for a 20 mg betahistine dose;
or about 3500 pg*hr/mL for a 40 mg betahistine dose.
[0011] In particular embodiments, the present disclosure is
directed to pharmaceutical compositions as described herein,
wherein after a single intranasal administration to a human, the
AUC.sub.0-inf ranges from about 80%-125% of: about 275 pg*hr/mL for
a 5 mg betahistine dose; about 700 pg*hr/mL for a 10 mg betahistine
dose; about 1630 pg*hr/mL for a 20 mg betahistine dose; or about
3940 pg*hr/mL for a 40 mg betahistine dose.
[0012] In still other embodiments, the present disclosure is
directed to methods of treating an inner ear dysfunction or inner
ear disorder, or treating or alleviating symptoms of an inner ear
disorder, or increasing cochlear blood flow or cerebral blood flow
in a subject comprising intranasally administering any of the
compositions disclosed herein to said subject.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 shows the betahistine concentration in plasma from 6
beagle dogs following intranasal administration of a single dose of
betahistine dihydrochloride 4, 20 or 80 mg over time.
[0014] FIG. 2 shows the concentration of 2-pyridylacetic acid
(2-PAA) in plasma from 6 beagle dogs following intranasal
administration of a single dose of betahistine dihydrochloride 4,
20 or 80 mg over time.
[0015] FIG. 3 shows the peak concentration C.sub.max of betahistine
in plasma from 24 healthy volunteers following intranasal
administration of a single dose of betahistine dihydrochloride 5,
10, 20 or 40 mg (whiskers=standard deviation).
[0016] FIG. 4 shows the peak concentration C.sub.max of
2-pyridylacetic acid (2-PAA) in plasma 24 from healthy volunteers
following intranasal administration of a single dose of betahistine
dihydrochloride 5, 10, 20 or 40 mg (whiskers=standard
deviation).
[0017] FIG. 5 shows the median betahistine concentration in plasma
over time from 8 beagle dogs following intranasal administration of
a single dose of betahistine dihydrochloride at a dose of 40, 80,
or 120 mg.
[0018] FIG. 6 shows the mean betahistine concentration in plasma
over time from 8 beagle dogs following intranasal administration of
a single dose of betahistine dihydrochloride at a dose of 40, 80,
or 120 mg.
[0019] FIG. 7 shows the median betahistine concentration in plasma
over time from 8 beagle dogs following oral administration of
betahistine.
[0020] FIG. 8 shows the mean betahistine concentration in plasma
over time from 8 beagle dogs following oral administration of
betahistine.
[0021] FIG. 9 shows the median betahistine concentration in plasma
over time from 8 beagle dogs following intravenous administration
of betahistine.
[0022] FIG. 10 shows the mean betahistine concentration in plasma
over time from 8 beagle dogs following intravenous administration
of betahistine.
DETAILED DESCRIPTION
[0023] While the following terms are believed to be well understood
by one of ordinary skill in the art, the following definitions are
set forth to facilitate explanation of the presently disclosed
subject matter.
[0024] Throughout the present specification, the terms "about"
and/or "approximately" may be used in conjunction with numerical
values and/or ranges. The term "about" is understood to mean those
values near to a recited value. For example, "about 40 [units]" may
mean within .+-.25% of 40 (e.g., from 30 to 50), within .+-.20%,
.+-.15%, .+-.10%, .+-.9%, .+-.8%, .+-.7%, .+-.6%, .+-.5%, .+-.4%,
.+-.3%, .+-.2%, .+-.1%, less than .+-.1%, or any other value or
range of values therein or therebelow. In other contexts, the term
"about" may refer to a value intermediate between adjacent values
in a numerical sequence. Furthermore, the phrases "less than about
[a value]" or "greater than about [a value]" should be understood
in view of the definition of the term "about" provided herein. The
terms "about" and "approximately" may be used interchangeably.
[0025] Throughout the present specification, numerical ranges are
provided for certain quantities. It is to be understood that these
ranges comprise all subranges therein. Thus, the range "from 50 to
80" includes all possible ranges therein (e.g., 51-79, 52-78,
53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a
given range may be an endpoint for the range encompassed thereby
(e.g., the range 50-80 includes the ranges with endpoints such as
55-80, 50-75, etc.).
[0026] The term "a" or "an" refers to one or more of that entity;
for example, "a kinase inhibitor" refers to one or more kinase
inhibitors or at least one kinase inhibitor. As such, the terms "a"
(or "an"), "one or more" and "at least one" are used
interchangeably herein. In addition, reference to "an inhibitor" by
the indefinite article "a" or "an" does not exclude the possibility
that more than one of the inhibitors is present, unless the context
clearly requires that there is one and only one of the
inhibitors.
[0027] As used herein, the verb "comprise" as is used in this
description and in the claims and its conjugations are used in its
non-limiting sense to mean that items following the word are
included, but items not specifically mentioned are not excluded.
The present invention may suitably "comprise", "consist of", or
"consist essentially of", the steps, elements, and/or reagents
described in the claims.
[0028] It is further noted that the claims may be drafted to
exclude any optional element. As such, this statement is intended
to serve as antecedent basis for use of such exclusive terminology
as "solely", "only" and the like in connection with the recitation
of claim elements, or the use of a "negative" limitation.
[0029] The term "treat," "treated," "treating" or "treatment"
includes the diminishment or alleviation of at least one symptom
associated or caused by the state, disorder or disease being
treated. Treatment can be diminishment of one or several symptoms
of a disorder or complete eradication of a disorder or a disease.
Similarly, the term "prophylaxis" refers to the partial or total
prevention of symptoms by administration of the active agent prior
to the expected initiation of such symptoms.
[0030] As used herein, the term "subject," "individual" or
"patient" is used interchangeably and refers to a vertebrate,
preferably a mammal. Non-limiting examples include mice, dogs,
rabbits, farm animals, sport animals, pets, and humans.
[0031] As used herein, "therapeutically effective amount" or an
"effective amount" indicates an amount that results in a desired
pharmacological and/or physiological effect for the condition. The
effect may be prophylactic in terms of completely or partially
preventing a condition or symptom thereof and/or may be therapeutic
in terms of a partial or complete cure for the condition and/or
adverse effect attributable to the condition.
[0032] As used herein, the term "pharmaceutically acceptable salt
of betahistine" refers to pharmaceutically acceptable acid addition
salts of betahistine, especially those which are known to be
non-toxic and are commonly used in the art of pharmaceutical
formulation. In one embodiment, betahistine salt is an acid
addition salt where the non-limiting example of the acid is
selected from: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid,
2-hydroxyethanesulfonic acid, 2-oxoglutaric acid,
4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic
acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid,
benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+),
capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic
acid (octanoic acid), carbonic acid, cinnamic acid, citric acid,
cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid,
ethanesulfonic acid, formic acid, fumaric acid, galactaric acid,
gentisic acid, glucoheptonic acid (D), gluconic acid (D),
glucuronic acid (D), glutamic acid, glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic
acid, hydrochloric acid, isobutyric acid, lactic acid (DL),
lactobionic acid, lauric acid, maleic acid, malic acid (-L),
malonic acid, mandelic acid (DL), methanesulfonic acid,
naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic
acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic
acid (-L), salicylic acid, sebacic acid, stearic acid, succinic
acid, sulfuric acid, tartaric acid (+L), thiocyanic acid,
toluenesulfonic acid (p), or undecylenic acid. In another
embodiment, suitable betahistine salts also include, but are not
limited to, hydrochloride, hydrobromide, hydroiodide, tartrate,
mesylate, citrate, phosphate, acetate, pamoate/embonate, nitrate,
lactate, sulfate, methylsulfate, fumarate, oxalate, phthalate,
maleate, and succinate. Further, betahistine salts may be a
mono-salt or a bis-salt. In one embodiment, betahistine
hydrochloride can be a betahistine monohydrochloride or a
betahistine bis-hydrochloride.
[0033] In one embodiment of the present disclosure, the betahistine
or a pharmaceutically acceptable salt thereof can be formulated in
any form suited for administration by various pathways including
nasally (e.g., solution, spray, drops, aerosol, gels, dry powders),
orally (e.g., tablets, capsules, granules, syrups, elixirs, or
powders) sublingually, buccally, parenterally (e.g., subcutaneous,
intravenous, intramuscular, intrathecal, or intracisternal
injection), or infusion techniques (e.g., as sterile injectable
aqueous or non-aqueous solutions or suspensions), topically (e.g.,
drug-releasing skin patch, cream or ointment), intravaginally, by
drench, transdermally, intradermally, pulmonary, by intra-uterine,
by the use of an aerosol, or rectally (e.g., suppositories, in
dosage unit formulations containing nontoxic, pharmaceutically
acceptable vehicles or diluents). In one embodiment, the
betahistine or a pharmaceutically acceptable salt thereof is
formulated in any form suited for nasal or intranasal
administration.
[0034] In one embodiment of the present disclosure, a
pharmaceutical composition is provided comprising betahistine
hydrochloride. In another embodiment, the pharmaceutical
composition is provided comprising betahistine monohydrochloride.
In another embodiment, the pharmaceutical composition is provided
comprising betahistine dihydrochloride.
[0035] In one embodiment, the pharmaceutical composition comprises
a particular polymorph of a betahistine or a pharmaceutically
acceptable salt thereof. In one embodiment, the pharmaceutical
composition comprises a particular polymorph of a betahistine or a
pharmaceutically acceptable salt thereof is formulated in any form
suited for nasal or intranasal administration.
[0036] In one embodiment of the present disclosure, a
pharmaceutical composition is provided comprising betahistine or a
pharmaceutically acceptable salt thereof. In particular
embodiments, the pharmaceutical compositions of the present
disclosure comprise solutions or suspensions of betahistine, or a
pharmaceutically acceptable salt thereof. In another embodiment, a
pharmaceutical composition is provided comprising betahistine or a
pharmaceutically acceptable salt thereof and one or more viscosity
agents or one or more pharmaceutically acceptable viscosity
enhancing agents. Non limiting examples of suitable viscosity
agents or viscosity enhancing agents include polyvinyl pyrrolidone,
polyvinyl alcohol, methylcellulose, carboxymethyl cellulose-Na,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, polyethylene-oxide, Carbopol, polyethylene glycol,
propylene glycol, glycerin, alginates, carrageenan, pectins,
maltodextrin, sodium starch glycolate, tragacanth gum; gum arabic,
microcrystalline cellulose and derivatives thereof. In one
embodiment, the viscosity enhancing agent is polyvinyl
pyrrolidone.
[0037] In another embodiment, the present disclosure is directed to
a pharmaceutical composition comprising betahistine or a
pharmaceutically acceptable salt thereof and one or more viscosity
agents is an intranasal pharmaceutical composition. In one
embodiment, the one or more viscosity agents in the formulation for
intranasal administration allows the formulation to be retained at
the application site long enough for the betahistine or a
pharmaceutically acceptable salt thereof to be absorbed. In another
embodiment, the presence of one or more viscosity agents in the
formulation for intranasal administration does not prevent the
formulation to be sprayed into the nasal cavity.
[0038] In one embodiment, the pharmaceutical compositions of the
present disclosure have a viscosity in the range of about 0.1 cps
to about 1000 cps or about 1 cps to about 100 cps. In one
embodiment, the viscosity of the pharmaceutical composition of the
present disclosure is about 0.1 cps, about 0.5 cps, about 1 cps,
about 5 cps, about 10 cps, about 15 cps, about 20 cps, about 25
cps, about 30 cps, about 40 cps, about 45 cps, about 50 cps, about
55 cps, about 60 cps, about 65 cps, about 70 cps, about 75 cps,
about 80 cps, about 85 cps, about 90 cps, about 95 cps, about 100
cps, about 105 cps, about 110 cps, about 115 cps, about 120 cps,
about 125 cps, about 130 cps, about 135 cps, about 140 cps, about
145 cps, about 150 cps, about 175 cps, about 200 cps, about 250
cps, about 300 cps, about 350 cps, about 400 cps, about 450 cps,
about 500 cps, about 550 cps, about 600 cps, about 650 cps, about
700 cps, about 750 cps, about 800 cps, about 850 cps, about 900
cps, about 950 cps, or about 1000 cps. In one embodiment, the
viscosity of the pharmaceutical compositions described herein can
be measured by the USP <911> Viscosity method.
[0039] In one embodiment, the pharmaceutical compositions of the
present disclosure for nasal delivery have a viscosity of about 0.5
cps to about 10.5 cps, about 1 cps to about 10 cps, or about 1 cps
to about 7 cps. In one embodiment, the pharmaceutical composition
of the present disclosure for nasal delivery has a viscosity of
about 0.5 cps, about 0.6 cps, about 0.7 cps, about 0.8 cps, about
0.9 cps, about 1.0 cps, about 1.1 cps, about 1.2 cps, about 1.3
cps, about 1.4 cps, about 1.5 cps, about 1.6 cps, about 1.7 cps,
about 1.8 cps, about 1.9 cps, about 2.0 cps, about 2.1 cps, about
2.2 cps, about 2.3 cps, about 2.4 cps, about 2.5 cps, about 2.6
cps, about 2.7 cps, about 2.8 cps, about 2.9 cps, about 3.0 cps,
about 3.1 cps, about 3.2 cps, about 3.3 cps, about 3.4 cps, about
3.5 cps, about 3.6 cps, about 3.7 cps, about 3.8 cps, about 3.9
cps, about 4.0 cps, about 4.1 cps, about 4.2 cps, about 4.3 cps,
about 4.4 cps, about 4.5 cps, about 4.6 cps, about 4.7 cps, about
4.8 cps, about 4.9 cps, about 5.0 cps, about 5.1 cps, about 5.2
cps, about 5.3 cps, about 5.4 cps, about 5.5 cps, about 5.6 cps,
about 5.7 cps, about 5.8 cps, about 5.9 cps, about 6.0 cps, about
6.1 cps, about 6.2 cps, about 6.3 cps, about 6.4 cps, about 6.5
cps, about 6.6 cps, about 6.7 cps, about 6.8 cps, about 6.9 cps,
about 7.0 cps, about 7.1 cps, about 7.2 cps, about 7.3 cps, about
7.4 cps, about 7.5 cps, about 7.6 cps, about 7.7 cps, about 7.8
cps, about 7.9 cps, about 8.0 cps, about 8.1 cps, about 8.2 cps,
about 8.3 cps, about 8.4 cps, about 8.5 cps, about 8.6 cps, about
8.7 cps, about 8.8 cps, about 8.9 cps, about 9.0 cps, about 9.1
cps, about 9.2 cps, about 9.3 cps, about 9.4 cps, about 9.5 cps,
about 9.6 cps, about 9.7 cps, about 9.8 cps, about 9.9 cps, about
10.0 cps, about 10.1 cps, about 10.2 cps, about 10.3 cps, about
10.4 cps, about 10.5 cps, or any range between any of these values.
In one embodiment, the pharmaceutical compositions of the present
disclosure for nasal delivery are in an intranasal composition. In
one embodiment, the viscosity of the pharmaceutical compositions
described herein can be measured by the USP <911> Viscosity
method.
[0040] In one embodiment, the pharmaceutical compositions of the
present disclosure comprise one or more pharmaceutically acceptable
moisturizing agents. Non-limiting examples of such moisturizing
agents include glycerin, ethylene glycol, propylene glycol,
propylene glycol 400, hexalene glycol, butylene glycol, dextrose,
glyceryl triacetate, polydextrose, glycerol, glyceryl triacetate,
sorbitol, and mannitol. In various embodiments, the pharmaceutical
compositions of the present disclosure can include mixtures of
pharmaceutically acceptable moisturizing agents.
[0041] In one embodiment, the one or more moisturizing agents are
selected from glycerin, polyethylene glycol 400 and propylene
glycol. In one embodiment, the pharmaceutical compositions of the
present disclosure comprise glycerin. In another embodiment, the
pharmaceutical composition of the present disclosure comprises
polyethylene glycol 400. In other embodiments, the pharmaceutical
composition of the present disclosure comprises propylene glycol.
In some embodiments, the pharmaceutical compositions of the present
disclosure comprise glycerin, polyethylene glycol 400 and propylene
glycol.
[0042] In one embodiment, the pharmaceutical compositions of the
present disclosure comprising one or more pharmaceutically
acceptable moisturizing agents are intranasal pharmaceutical
compositions. In one embodiment, one or more moisturizing agents in
the intranasal pharmaceutical composition for intranasal
administration moisturize the nasal mucosa, nasal tissues, and/or
nasal membrane. In one embodiment, one or more moisturizing agents
in the intranasal pharmaceutical composition for intranasal
administration reduce irritation in the nasal cavity after
administration. In some embodiments, the intranasal pharmaceutical
composition of the present disclosure comprises glycerin,
polyethylene glycol 400 and propylene glycol.
[0043] In another embodiment, a pharmaceutical composition is
provided comprising betahistine or a pharmaceutically acceptable
salt thereof, one or more viscosity agents, and one or more
moisturizing agent. In one embodiment, the pharmaceutical
composition is an intranasal pharmaceutical composition.
[0044] In one embodiment, the pharmaceutical compositions of the
present disclosure comprise one or more pharmaceutically acceptable
carriers and/or one or more pharmaceutically acceptable
excipients.
[0045] In one embodiment, the pharmaceutical compositions of the
present disclosure further comprise one or more additives,
including but not limited to, preservatives, agents influencing
osmolarity, complexing agents (such as, for example, sodium
edetate), surfactants, agents which influence the pH and tonicity,
and sensory masking agents. In one embodiment, the pharmaceutical
composition of the present disclosure for intranasal delivery
further comprises one or more additives, including but not limited
to, preservatives, agents influencing osmolarity, complexing agents
(such as, for example, sodium edetate), surfactants, agents which
influence the pH and tonicity, and sensory masking agents.
[0046] Non-limiting examples of additives and/or excipients include
benzyl alcohol, benzalkonium chloride, carboxymethyl cellulose
sodium/cellulose microcrystalline, propylparaben, methylparaben,
phenethyl alcohol, chlorobutanol, EDTA, ethanol, ascorbic acid,
hydrochloric acid, sulfuric acid, sodium hydroxide, potassium
phosphate, sodium phosphate, sodium citrate, sodium chloride,
anhydrous dextrose, butylated hydroxyanisole, butylated,
hydroxytoluene, PEG 400, PEG 3500, polyoxyl 400 stearate,
polysorbate 20, polysorbate 80, glycerin, propylene glycol,
glyceryl triacetate, glycerol, ethylene glycol, sorbitol, mannitol,
and alginates, carrageenan, pectins, tragacanth gum, gum
arabic.
[0047] For the purposes of this disclosure, the pharmaceutical
composition comprising betahistine or a pharmaceutically acceptable
salt thereof, may be formulated for administration by a variety of
means including orally, parenterally, by inhalation spray,
topically, or rectally in formulations containing pharmaceutically
acceptable carriers, adjuvants and vehicles. The term parenteral as
used here includes subcutaneous, intravenous, intramuscular, and
intraarterial injections with a variety of infusion techniques.
Intraarterial and intravenous injections as used herein include
administration through catheters.
[0048] The pharmaceutical composition disclosed herein can be
formulated in accordance with the routine procedures adapted for
desired administration route. Accordingly, a pharmaceutical
composition herein can take such forms as suspensions, solutions or
emulsions in oily or aqueous vehicles, and can contain formulatory
agents such as suspending, stabilizing and/or dispersing agents.
Alternatively, the betahistine or a pharmaceutically acceptable
salt thereof can be in powder form for constitution with a suitable
vehicle, e.g., sterile pyrogen-free water, before use. Suitable
formulations for each of these methods of administration can be
found, for example, in Remington: The Science and Practice of
Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams &
Wilkins, Philadelphia, Pa.
[0049] In one embodiment, pharmaceutically acceptable carriers are
well known to those skilled in the art and include, but are not
limited to, buffer solutions, saline, and water. In one embodiment,
a pharmaceutically acceptable carrier includes about 0.01 to about
0.1 M phosphate buffer or saline (e.g., 0.8% saline). In one
embodiment, the buffer solution comprises sodium phosphate dibasic
and sodium phosphate monobasic. In such embodiments, the buffering
agent adjusts the pH of the composition within a range suitable to
permit rapid absorption of betahistine through the nasal mucosa,
and to minimize irritation. For example, pH can be controlled to
fall within a range of about 4 to about 9, including pH values of
about 4, about 4.2, about 4.4, about 48, about 5, about 5.2, about
5.4, about 5.6, about 5.8, about 6, about 6.2, about 6.4, about
6.8, about 7, about 7.2, about 7.4, about 7.6, about 7.8, about 8,
about 8.2, about 8.4, about 8.6, about 8.8, or about 9, inclusive
of all ranges between any of these values. In one embodiment, the
pharmaceutical composition of the present disclosure has a pH value
of about 5. In another embodiment, the pharmaceutical composition
of the present disclosure having a pH value of about 5 demonstrates
improved solubility and stability of betahistine or a
pharmaceutically acceptable salt thereof when compared to a
composition with greater pH value.
[0050] Such pharmaceutically acceptable carriers can be aqueous or
non-aqueous solutions, suspensions and emulsions. Examples of
non-aqueous solvents suitable for use in the present application
include, but are not limited to, propylene glycol, polyethylene
glycol, vegetable oils such as olive oil, and injectable organic
esters such as ethyl oleate.
[0051] Aqueous carriers suitable for use in the present application
include, but are not limited to, water, alcoholic/aqueous solutions
(such as ethanol/water), glycerol and or glycerol/aqueous mixtures,
emulsions or suspensions, including saline and buffered media. Oral
carriers can be elixirs, syrups, capsules, tablets and the
like.
[0052] Liquid carriers suitable for use in the present application
can be used in preparing solutions, suspensions, or emulsions. The
active ingredient can be dissolved or suspended in a
pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fats. The liquid carrier can contain other suitable
pharmaceutical additives such as solubilizers, emulsifiers,
buffers, preservatives, sweeteners, flavoring agents, suspending
agents, thickening agents, colors, viscosity regulators,
stabilizers or osmo-regulators.
[0053] Liquid carriers suitable for use in the present application
include, but are not limited to, water (partially containing
additives as above, e.g. cellulose derivatives, preferably sodium
carboxymethyl cellulose solution), alcohols (including monohydric
alcohols and polyhydric alcohols, e.g. glycols) and their
derivatives, and oils (e.g. fractionated coconut oil and arachis
oil). If the compositions of the present invention are administered
from pressurized containers (e.g., pressurized, metered dose
dispensers), the liquid carrier for pressurized compositions
disclosed herein can be a halogenated hydrocarbon, hydrocarbon,
carbon dioxide, or other pharmaceutically acceptable
propellant.
[0054] Solid carriers suitable for use in the present application
(e.g., when the compositions are provided as a intranasal dry
powder) include, but are not limited to, inert substances such as
lactose, starch, glucose, methyl-cellulose, magnesium stearate,
dicalcium phosphate, mannitol and the like.
[0055] Flavoring agents and flavor enhancers may make the dosage
form more palatable to the patient, in the event that some of the
intranasally administered composition is ingested. Common flavoring
agents and flavor enhancers for pharmaceutical products that may be
included in the composition and/or combination of the present
invention include maltol, vanillin, ethyl vanillin, menthol, citric
acid, fumaric acid, ethyl maltol, and tartaric acid.
[0056] Sensory masking agent can be used to taste mask and/or odor
mask sensation in connection with the administration of the
pharmaceutical composition. In one embodiment, odor masking agent
can include scented aromatic masking agent. In one embodiment, any
known sensory masking agents which is known in the pharmaceutical
literature can be considered.
[0057] Compositions of the present disclosure may also include a
dye using any pharmaceutically acceptable colorant to improve their
appearance and/or facilitate patient identification of the product
and unit dosage level in liquid pharmaceutical compositions of the
present invention where the components are dissolved or suspended
in a liquid carrier such as water, vegetable oil, alcohol,
polyethylene glycol, propylene glycol, or glycerin.
[0058] For example, formulations for parenteral administration can
contain as common excipients sterile water or saline, polyalkylene
glycols such as polyethylene glycol, oils of vegetable origin,
hydrogenated naphthalenes and the like. In particular,
biocompatible, biodegradable lactide polymer, lactide/glycolide
copolymer, or polyoxyethylene-polyoxypropylene copolymers can be
useful excipients to control the release of active compounds.
Formulations for inhalation administration contain as excipients,
for example, lactose, or can be aqueous solutions containing, for
example, polyoxyethylene-9-auryl ether, glycocholate and
deoxycholate, or oily solutions for administration in the form of
nasal drops, or as a gel to be applied intranasally. Formulations
for parenteral administration can also include glycocholate for
buccal administration, methoxysalicylate for rectal administration,
or citric acid for vaginal administration.
[0059] Liquid pharmaceutical compositions and/or combinations may
contain emulsifying agents to disperse uniformly throughout the
composition and/or combination an active ingredient or other
excipient that is not soluble in the liquid carrier. Emulsifying
agents that may be useful in liquid compositions and/or
combinations of the present invention include, for example,
gelatin, egg yolk, casein, cholesterol, acacia, tragacanth,
chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol,
and cetyl alcohol.
[0060] Sweetening agents such as aspartame, lactose, sorbitol,
saccharin, sodium saccharin, sucrose, aspartame, fructose,
mannitol, and invert sugar may be added to improve the taste.
[0061] Preservatives and chelating agents such as alcohol,
quaternary ammonium compounds such as benzethonium chloride,
benzoxonium chloride, benzododecinium bromide,
alkyltrimethilammonium bromide, cetrimonium bromide, benzalkonium
chloride, phenylethyl alcohol, benzoic acid and esters and salts
thereof, e.g. C.sub.1-C.sub.7-alkyl esters of 4-hydroxybenzoic
acid, such as methyl 4-hydroxybenzoate, sodium methyl
4-hydroxybenzoate or propyl 4-hydroxybenzoate, butylated hydroxyl
toluene, butylated hydroxyanisole, cetylpyridinium chloride,
cetrimide; parabens and derivatives such as propylparaben or
methylparaben; alkyl acids, such as potassium sorbate, sorbic acid,
calcium sorbate, sodium sorbate; biguanides, e.g. chlorhexidine or
nasally acceptable salts thereof, e.g. chlorhexidine digluconate,
chlorhexidine acetate or chlorhexidine chloride, 2-phenoxyethanol;
boric acids; phenols such as 4-chlorocresol, 4-chloroxylenol,
dichlorophene or hexachlorophene and chelators such as
ethylenediamine tetraacetic acid (EDTA) or
ethylenediamine-N,N'-disuccinic acid (EDDS) may be added at levels
safe for administration to improve storage stability.
[0062] A liquid composition and/or combination may also contain
additives or excipients such as gluconic acid, lactic acid, citric
acid or acetic acid, sodium gluconate, sodium lactate, sodium
citrate, or sodium acetate. Selection of excipients and the amounts
used may be readily determined by the formulation scientist based
upon experience and consideration of standard procedures and
reference works in the field.
[0063] The pharmaceutical compositions and/or pharmaceutical
combinations of the invention may be in the form of an aqueous or
oleaginous suspension. In one embodiment, the pharmaceutical
composition and/or pharmaceutical combinations of the invention may
be in the form of a sterile aqueous or oleaginous suspension. This
suspension may be formulated according to the known art using
suitable dispersing or wetting agents and suspending agents. The
sterile solution or suspension may be dissolved or dispersed in a
non-toxic pharmaceutically acceptable diluent or solvent, such as a
solution in 1,3-butane-diol or prepared as a lyophilized powder for
delivery as a dry powder. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile fixed oils
may conventionally be employed as a solvent or suspending medium.
For this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides.
[0064] Dosage forms include powders or liquids capable of
administration via vaporization or an aerosol, or as a dry powder.
Dosing can be controlled through the use of a metered pump
dispensing device, such as are known in the art.
[0065] In one embodiment of the present disclosure, the betahistine
or a pharmaceutically acceptable salt thereof can be formulated in
any way suited for nasal or intranasal administration. In one
embodiment of the present disclosure, an intranasal pharmaceutical
composition is provided comprising betahistine hydrochloride. In
another embodiment, the intranasal pharmaceutical composition is
provided comprising betahistine monohydrochloride. In another
embodiment, the intranasal pharmaceutical composition is provided
comprising betahistine dihydrochloride.
[0066] In another embodiment, an intranasal pharmaceutical
composition comprises betahistine free base. In another embodiment,
an intranasal pharmaceutical composition comprises betahistine
pharmaceutically acceptable salts selected from betahistine
hydrochloride, betahistine dihydrochloride, betahistine fumarate,
betahistine maleate, betahistine tartrate, betahistine citrate,
betahistine succinate, betahistine phthalate and betahistine
mesylate, betahistine hydrobromide, betahistine hydroiodide,
betahistine mesylate, betahistine phosphate, betahistine acetate,
betahistine pamoate/embonate, betahistine nitrate, betahistine
lactate, betahistine sulfate, betahistine methylsulfate,
betahistine oxalate, or any other pharmaceutically acceptable
betahistine salt disclosed herein or known in the art.
[0067] In one embodiment, to improve nasal delivery and retention,
the betahistine or a pharmaceutically acceptable salt thereof may
be encapsulated with cyclodextrins, or formulated with other agents
expected to enhance delivery and retention in the nasal mucosa.
[0068] In one embodiment, the present disclosure provides sustained
or controlled release formulations of betahistine. For example,
bioadhesive polymers have shown good potential for nasal
formulations and can control the rate and extent of drug release.
Additionally, the prolonged contact time afforded by bioadhesive
polymers at the site of absorption can improve drug
bioavailability. Thus, nasal formulations comprising bioadhesive
polymers, e.g. chitosan microspheres, are contemplated by the
present disclosure. Various biocompatible and biodegradable
polymers that may be used to formulate sustained release nasal
compositions include poly-vinyl alcohol, chitosan, carbopol,
alginate, hydroxypropyl methylcellulose, hydroxypropyl cellulose,
starch and gellan gum. In some embodiments, liposomal formulations
may also be used to provide sustained release. In other
embodiments, nasal microparticles or microspheres comprising
albumin, starch, dextran and/or chitosan may be used to provide
sustained release. These and other sustained nasal drug delivery
systems are reviewed by Ghori et al. (American Journal of
Pharmacological Sciences, 2015, Vol. 3, No. 5, 110-119), which is
incorporated by reference herein in its entirety for all
purposes.
[0069] In some embodiments, controlled release nasal delivery
systems disclosed in U.S. Pat. No. 8,574,622, which is incorporated
by reference herein in its entirety for all purposes, may be used
to provide sustained release of the active.
[0070] In some embodiments, formulations comprising absorption
enhancers may be used to provide sustained release. The purpose of
absorption enhancement in intranasal drug delivery is to facilitate
or increase the uptake of the drug. This can be achieved by either
prolonging the residence time to obtain a larger time frame for
absorption, or by increasing the permeation of the mucosal tissue.
Absorption enhancement is achieved through mucoadhesion or in situ
gelling for a prolonged residence time, sometimes a combination
thereof, or enhancing permeation by weakening cellular junctions or
increasing the fluidity of membrane bilayers. Accordingly,
formulations comprising mucoadhesive excipients and/or in situ
gelling agents may be used for intranasal delivery of betahistine.
For example, in one embodiment, sustained release formulations
comprising mucoadhesive excipients such as carbomers, cellulose
derivates, starch derivates, or chitosans may be used in the
present invention.
[0071] In another embodiment, sustained release formulations are in
the form of in situ nasal gelling systems comprising stimulus
responsive polymers. Stimulus responsive polymers include polymers
that alter the rheological characteristics of in situ gelling
formulations upon contact with the nasal mucosa due to changes in
temperature, pH, or ions. Examples of stimulus responsive polymers
or in situ gelling agents include, but are not limited to,
poloxamers, pectin, and chitosan-based polymers. In one embodiment,
in situ gelling systems may further comprise mucoadhesive
excipients such as carbopol 934P, chitosan, sodium carboxymethyl
cellulose (NaCMC), hydroxypropyl methylcellulose (HPMC),
hydroxypropyl cellulose and methylcellulose. In some embodiments,
nasal formulations comprising stimuls responsive polymers, which
may optionally further comprise mucoadhesive excipients, e.g. those
disclosed in Chonkar et al., Indian J Pharm Sci., 2015 July-August;
77(4): 367-375, incorporated by reference herein in its entirety
for all purposes, may be used as sustained release formulations to
carry out the present invention. In other embodiments, mucoadhesive
microspheres comprising betahistine dihydrochloride disclosed in
Pilicheva et al. (International Journal of Drug Delivery, 2013,
5(4): 389-401), incorporated by reference herein in its entirety
for all purposes, may be adapted for intransal delivery of
betahistine in accordance with the present invention.
[0072] In some embodiments, formulations comprising absorption
enhancers such as alkyl glycosides disclosed in U.S. Pre-Grant
Publication Nos. 2006/0045868, 2006/0045869, 2008/0299079 or
formulations comprising soybean-derived steryl glycoside and sterol
mixtures as absorption enhancers (Ando et al., Biological and
Pharmaceutical Bulletin, 21(8), 862-865) may be used to provide
sustained release, each of these documents is herein incorporated
by reference for all purposes. In some other embodiments,
formulations comprising micelles of sodium glycocholate or micelles
of sodium glycocholate mixed with fatty acid (e.g. linoleic acid)
as absorption enhancers may be used as sustained release
formulations. Other examples of absorption enhancers include
cyclodextrins, phospholipids, and chitosans.
[0073] Exemplary nasal formulations based on thermogelling polymers
such as poloxamers are disclosed by Sharma et al. (Drug Dev Ind
Pharm. 2014 July; 40(7):869-78); Cho et al. (J Pharm Sci. 2011
February; 100(2):681-91); Choi et al. (Int Forum Allergy Rhinol.
2017 July; 7(7):705-711); and Balakrishnan et al. (Molecules. 2015
Mar. 4; 20(3):4124-35), each of these documents is incorporated by
reference herein in its entirety for all purposes. Formulations
disclosed in these references may be adapted for intransal delivery
of betahistine in accordance with the present invention.
[0074] In one embodiment, the pharmaceutical composition of the
present disclosure comprises ingredients disclosed in Table 1. In
another embodiment, the pharmaceutical composition of the present
disclosure is substantially similar to the composition disclosed in
Table 1. In one embodiment, the pharmaceutical composition of the
present disclosure comprises ingredients disclosed in Table 1 with
varying amounts of each ingredient.
TABLE-US-00001 TABLE 1 Sample Betahistine Formulation Concentration
Ingredient Amount (mg/ml) Betahistine dihydrochloride 5 g* 50.0
Benzalkonium chloride 20 mg 0.2 Glycerin 100 mg 1.0 Edetate
Disodium 20 mg 0.2 Polyvinyl Pyrrolidone 1.25 g 12.5 Polyethylene
Glycol 400 3.75 g 37.5 Sodium Phosphate Dibasic 97.5 mg 0.975
Propylene Glycol 2 g 20 Sodium Phosphate Monobasic 552.5 mg 5.525
1M Sodium Hydroxide 4.38 mL** pH 5.0 Water for Injection To 100 mL
For 200 mg/mL betahistine dihydrochloride formulation, *20 g of
betahistine dihydrochloride and **9.3 mL 1M sodium hydroxide can be
substituted.
Pharmacokinetics
[0075] In one embodiment, the pharmaceutical composition of the
present disclosure provides detectable C.sub.max of betahistine in
human plasma concentration after single dose administration of the
pharmaceutical composition of the present disclosure. In one
embodiment, the C.sub.max of betahistine in human plasma
concentration after single dose administration of the
pharmaceutical composition of the present disclosure is at least
about 0.2 ng/mL or at least about 0.5 ng/mL. In one embodiment, the
C.sub.max is measured after a single dose administration of about 1
mg to about 250 mg of betahistine or a pharmaceutically acceptable
salt. In one embodiment, the C.sub.max is measured after a single
dose administration of about 5 mg, about 10 mg, about 20 mg, about
30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80
mg, about 90 mg, about 100 mg, about 150 mg, or about 200 mg of
betahistine or a pharmaceutically acceptable salt. In other
embodiments, the C.sub.max for a 5 mg betahistine dose,
administered intranasally, ranges from about 80% to about 125% of
about 640 pg/mL; about 80% to about 125% of about 2000 pg/mL for a
10 mg betahistine dose, administered intranasally; about 80% to
about 125% of about 4000 pg/mL for a 20 mg betahistine dose,
administered intranasally; and about 80% to about 125% of about
10500 pg/mL for a 40 mg betahistine days, administered
intranasally. In other embodiments, the C.sub.max for a 5 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 230 to about 1260 pg/mL; about 80% to about
125% of about 790 to about 3470 pg/mL for a 10 mg betahistine dose,
administered intranasally; about 80% to about 125% of about 1900 to
about 8300 pg/mL for a 20 mg betahistine dose, administered
intranasally; and about 80% to about 125% of about 8000 to about
16000 pg/mL for a 40 mg betahistine dose, administered
intranasally.
[0076] In one embodiment, the C.sub.max for a 5 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 500 pg/mL, 550 pg/mL, 600 pg/mL, 650 pg/mL, 700
pg/mL, 750 pg/mL, 800 pg/mL, 850 pg/mL, 900 pg/mL, 950 pg/mL, 1000
pg/mL, 1050 pg/mL, 1100 pg/mL, 1150 pg/mL, 1200 pg/mL, 1250 pg/mL,
1300 pg/mL, 1350 pg/mL, 1400 pg/mL, 1450 pg/mL, 1500 pg/mL, 1550
pg/mL, 1600 pg/mL, 1650 pg/mL, 1700 pg/mL, 1750 pg/mL, 1800 pg/mL,
1850 pg/mL, 1900 pg/mL, 1950 pg/mL, 2000 pg/mL, 2050 pg/mL, 2100
pg/mL, 2150 pg/mL, 2200 pg/mL, 2250 pg/mL, 2300 pg/mL, 2350 pg/mL,
2400 pg/mL, 2450 pg/mL, 2500 pg/mL, 2550 pg/mL, 2600 pg/mL, 2650
pg/mL, 2700 pg/mL, 2750 pg/mL, 2800 pg/mL, 2850 pg/mL, 2900 pg/mL,
2950 pg/mL, or about 3000 pg/mL.
[0077] In other embodiments, the C.sub.max for a 5 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 600 to about 3000 pg/mL, about 600 to about 2800
pg/mL, about 600 to about 2600 pg/mL, about 600 to about 2400
pg/mL, about 600 to about 2200 pg/mL, about 600 to about 2000
pg/mL, about 600 to about 1800 pg/mL, about 600 to about 1600
pg/mL, about 600 to about 1400 pg/mL, about 600 to about 1200
pg/mL, about 600 to about 1000 pg/mL, about 500 to about 2500
pg/mL, about 500 to about 2300 pg/mL, about 500 to about 2100
pg/mL, about 500 to about 1900 pg/mL, about 500 to about 1700
pg/mL, about 500 to about 1500 pg/mL, about 500 to about 1300
pg/mL, or about 500 to about 1100 pg/mL.
[0078] In one embodiment, the C.sub.max for a 10 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 1800 pg/mL, 2000 pg/mL, 2200 pg/mL, 2400 pg/mL, 2600
pg/mL, 2800 pg/mL, 3000 pg/mL, 3200 pg/mL, 3400 pg/mL, 3600 pg/mL,
3800 pg/mL, 4000 pg/mL, 4200 pg/mL, 4400 pg/mL, 4600 pg/mL, 4800
pg/mL, 5000 pg/mL, 5200 pg/mL, 5400 pg/mL, 5600 pg/mL, 5800 pg/mL,
6000 pg/mL, 6200 pg/mL, 6400 pg/mL, 6600 pg/mL, 6800 pg/mL, 7000
pg/mL, 7200 pg/mL, 7400 pg/mL, 7600, 7800 pg/mL, or about 8000
pg/mL.
[0079] In other embodiments, the C.sub.max for a 10 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 1800 to about 4500 pg/mL, about 2000 to about 5000
pg/mL, about 2200 to about 5500 pg/mL, about 2500 to about 5500
pg/mL, about 1600 to about 3000 pg/mL, about 1600 to about 3300
pg/mL, or about 1600 to about 3500 pg/mL.
[0080] In one embodiment, the C.sub.max for a 20 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 3600 pg/mL, 3800 pg/mL, 4000 pg/mL, 4200 pg/mL, 4400
pg/mL, 4600 pg/mL, 4800 pg/mL, 5000 pg/mL, 5200 pg/mL, 5400 pg/mL,
5600 pg/mL, 5800 pg/mL, 6000 pg/mL, 6200 pg/mL, 6400 pg/mL, 6600
pg/mL, 6800 pg/mL, 7000 pg/mL, 7200 pg/mL, 7400 pg/mL, 7600 pg/mL,
7800 pg/mL, 8000 pg/mL, 8200 pg/mL, 8400 pg/mL, 8600 pg/mL, 8800
pg/mL, or 9000 pg/mL.
[0081] In other embodiments, the C.sub.max for a 20 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 3000 to about 8000 pg/mL, about 3000 to about 7700
pg/mL, about 3000 to about 7500 pg/mL, about 3000 to about 7300
pg/mL, about 3000 to about 7100 pg/mL, about 3000 to about 6900
pg/mL, about 3000 to about 6700 pg/mL, about 3000 to about 6500
pg/mL, about 3000 to about 6300 pg/mL, about 3000 to about 6100
pg/mL, about 3000 to about 5800 pg/mL, about 3000 to about 5600
pg/mL, about 3000 to about 5400 pg/mL, about 3000 to about 5200
pg/mL, about 3000 to about 5000 pg/mL, about 3250 to about 8000
pg/mL, about 3250 to about 7750 pg/mL, about 3250 to about 7500
pg/mL, about 3250 to about 7250 pg/mL, about 3250 to about 7000
pg/mL, about 3250 to about 6800 pg/mL, about 3250 to about 6600
pg/mL, about 3250 to about 6400 pg/mL, about 3250 to about 6200
pg/mL, about 3250 to about 6000 pg/mL, about 3250 to about 5800
pg/mL, about 3250 to about 5600 pg/mL, about 3250 to about 5400
pg/mL, about 3250 to about 5200 pg/mL, about 3250 to about 5000
pg/mL, about 3250 to about 4800 pg/mL, about 3500 to about 8000
pg/mL, about 3500 to about 7800 pg/mL, about 3500 to about 7600
pg/mL, about 3500 to about 7400 pg/mL, about 3500 to about 7200
pg/mL, about 3500 to about 7000 pg/mL, about 3500 to about 6800
pg/mL, about 3500 to about 6600 pg/mL, about 3500 to about 6400
pg/mL, about 3500 to about 6200 pg/mL, about 3500 to about 6000
pg/mL, about 3500 to about 5800 pg/mL, about 3500 to about 5600
pg/mL, about 3500 to about 5300 pg/mL, about 3500 to about 5100
pg/mL, about 3700 to about 7500 pg/mL, about 3700 to about 7200
pg/mL, about 3700 to about 7000 pg/mL, about 3700 to about 6800
pg/mL, about 3700 to about 6500 pg/mL, about 3700 to about 6300
pg/mL, about 3700 to about 6100 pg/mL, about 3700 to about 5900
pg/mL, about 3700 to about 5700 pg/mL, about 3700 to about 5500
pg/mL, about 3700 to about 5300 pg/mL, or about 3700 to about 5100
pg/mL.
[0082] In one embodiment, the C.sub.max for a 40 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 8000 pg/mL, 8500 pg/mL, 9000 pg/mL, 9500 pg/mL, 9800
pg/mL, 10000 pg/mL, 10300 pg/mL, 10500 pg/mL, 10750 pg/mL, 11000
pg/mL, 11250 pg/mL, 11500 pg/mL, 11750 pg/mL, 12000 pg/mL, 12250
pg/mL, 12500 pg/mL, 12750 pg/mL, 13000 pg/mL, 13250 pg/mL, 13500
pg/mL, 13750 pg/mL, 14000 pg/mL, 14250 pg/mL, 14500 pg/mL, 14750
pg/mL, 15000 pg/mL, 15250 pg/mL, 15500 pg/mL, 15750 pg/mL, 16000
pg/mL, 16500 pg/mL, 17000 pg/mL, 17500 pg/mL, 18000 pg/mL, 18500
pg/mL, 19000 pg/mL, 19500 pg/mL, or 20000 pg/mL.
[0083] In other embodiments, the C.sub.max for a 40 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 8000 to about 20000 pg/mL, about 8000 to about 19000
pg/mL, about 8000 to about 18500 pg/mL, about 8000 to about 18000
pg/mL, about 8000 to about 17500 pg/mL, about 8000 to about 17000
pg/mL, about 8000 to about 16500 pg/mL, about 8000 to about 16000
pg/mL, about 8000 to about 15500 pg/mL, about 8000 to about 15000
pg/mL, about 8000 to about 14500 pg/mL, about 8000 to about 14000
pg/mL, about 8000 to about 13500 pg/mL, about 8000 to about 13000
pg/mL, about 8000 to about 12500 pg/mL, about 9000 to about 19500
pg/mL, about 9000 to about 19000 pg/mL, about 9000 to about 18500
pg/mL, about 9000 to about 18000 pg/mL, about 9000 to about 17500
pg/mL, about 9000 to about 17000 pg/mL, about 9000 to about 16500
pg/mL, about 9000 to about 16000 pg/mL, about 9000 to about 15500
pg/mL, about 9000 to about 15000 pg/mL, about 9000 to about 15000
pg/mL, about 9000 to about 14500 pg/mL, about 9000 to about 14000
pg/mL, about 9000 to about 13500 pg/mL, about 9000 to about 13000
pg/mL, about 10000 to about 18500 pg/mL, about 10000 to about 18000
pg/mL, about 10000 to about 17500 pg/mL, about 10000 to about 17000
pg/mL, about 10000 to about 16500 pg/mL, about 10000 to about 16000
pg/mL, about 10000 to about 15500 pg/mL, about 10000 to about 15000
pg/mL, about 10000 to about 14500 pg/mL, or about 10000 to about
14000 pg/mL.
[0084] In one embodiment, the C.sub.max for a 60 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 14000 pg/mL, 14250 pg/mL, 14500 pg/mL, 14750 pg/mL,
15000 pg/mL, 15250 pg/mL, 15500 pg/mL, 15750 pg/mL, 16000 pg/mL.
16250 pg/mL, 16500 pg/mL, 16750 pg/mL, 17000 pg/mL, 17250 pg/mL,
17500 pg/mL, 17750 pg/mL, 18000 pg/mL, 18250 pg/mL, 18500 pg/mL, or
19000 pg/mL.
[0085] In other embodiments, the C.sub.max for a 60 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 13500 to about 19000 pg/mL, about 13500 to about
18500 pg/mL, about 13500 to about 18250 pg/mL, about 13500 to about
18000 pg/mL, about 13500 to about 17750 pg/mL, about 13500 to about
17500 pg/mL, about 13500 to about 17250 pg/mL, about 13500 to about
17000 pg/mL, about 13500 to about 16500 pg/mL, about 13500 to about
16000 pg/mL, about 14000 to about 19000 pg/mL, about 14000 to about
18500 pg/mL, about 14000 to about 18250 pg/mL, about 14000 to about
18000 pg/mL, about 14000 to about 17750 pg/mL, about 14000 to about
17500 pg/mL, about 14000 to about 17250 pg/mL, about 14000 to about
17000 pg/mL, about 14000 to about 16500 pg/mL, about 14000 to about
16000 pg/mL, about 14500 to about 18500 pg/mL, about 14500 to about
18250 pg/mL, about 14500 to about 18000 pg/mL, about 14500 to about
17750 pg/mL, about 14500 to about 17500 pg/mL, about 14500 to about
17250 pg/mL, about 14500 to about 17000 pg/mL, or about 14500 to
about 16500 pg/mL.
[0086] In one embodiment, the C.sub.max for a 80 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 18000 pg/mL, 18500 pg/mL, 19000 pg/mL, 19250 pg/mL,
19500 pg/mL, 19750 pg/mL, 20000 pg/mL, 20250 pg/mL, 20500 pg/mL,
20750 pg/mL, 21000 pg/mL, 21250 pg/mL, 21500 pg/mL, 21750 pg/mL,
22000 pg/mL, 22250 pg/mL, 22500 pg/mL, 22750 pg/mL, 23000 pg/mL,
23250 pg/mL, 23500 pg/mL, 23750 pg/mL, or 24000 pg/mL.
[0087] In other embodiments, the C.sub.max for a 80 mg betahistine
dose, administered intranasally, ranges from about 80% to about
125% of about 18000 to about 25000 pg/mL, about 18000 to about
24500 pg/mL, about 18000 to about 24000 pg/mL, about 18000 to about
23750 pg/mL, about 18000 to about 23500 pg/mL, about 18000 to about
23250 pg/mL, about 18000 to about 23000 pg/mL, about 18000 to about
22750 pg/mL, about 18000 to about 22500 pg/mL, about 18000 to about
22250 pg/mL, about 18000 to about 22000 pg/mL, about 18500 to about
25000 pg/mL, about 18500 to about 24500 pg/mL, about 18500 to about
24000 pg/mL, about 18500 to about 23750 pg/mL, about 18500 to about
23500 pg/mL, about 18500 to about 23250 pg/mL, about 18500 to about
23000 pg/mL, about 18500 to about 22750 pg/mL, about 18500 to about
22500 pg/mL, about 18500 to about 22250 pg/mL, about 18500 to about
22000 pg/mL, about 19000 to about 25000 pg/mL, about 19000 to about
24500 pg/mL, about 19000 to about 24250 pg/mL, about 19000 to about
24000 pg/mL, about 19000 to about 23750 pg/mL, about 19000 to about
23500 pg/mL, about 19000 to about 23250 pg/mL, about 19000 to about
23000 pg/mL, about 19000 to about 22750 pg/mL, about 19000 to about
22500 pg/mL, about 19000 to about 22250 pg/mL, about 19000 to about
22000 pg/mL, about 19500 to about 24500 pg/mL, about 19500 to about
24250 pg/mL, about 19500 to about 24000 pg/mL, about 19500 to about
23750 pg/mL, about 19500 to about 23500 pg/mL, about 19500 to about
23250 pg/mL, about 19500 to about 23000 pg/mL, about 19500 to about
22750 pg/mL, about 19500 to about 22500 pg/mL, about 19500 to about
22250 pg/mL, or about 19500 to about 22000 pg/mL.
[0088] In one embodiment, the C.sub.max of betahistine in human
plasma concentration after single dose administration of the
intranasal pharmaceutical composition of the present disclosure is
at least about 0.2 ng/mL or at least about 0.5 ng/mL. In one
embodiment, the C.sub.max of betahistine in human plasma
concentration after single dose administration of the intranasal
pharmaceutical composition of the present disclosure is at least
about 0.2 ng/mL, at least about 0.3 ng/mL, at least about 0.4
ng/mL, at least about 0.5 ng/mL, at least about 0.6 ng/mL, at least
about 0.7 ng/mL, at least about 0.8 ng/mL, at least about 0.9
ng/mL, at least about 1 ng/mL, at least about 1.5 ng/mL, at least
about 2 ng/mL, at least about 2.5 ng/mL, at least about 3 ng/mL, at
least about 3.5 ng/mL, at least about 4 ng/mL, at least about 4.5
ng/mL, at least about 5 ng/mL, at least about 5.5 ng/mL, at least
about 6 ng/mL, at least about 7.5 ng/mL, at least about 8 ng/mL, at
least about 8.5 ng/mL, at least about 9 ng/mL, at least about 9.5
ng/mL, or at least about 10 ng/mL.
[0089] In one embodiment, the C.sub.max of betahistine in human
plasma concentration after single dose administration of the
intranasal pharmaceutical composition of the present disclosure is
at least about 10 ng/mL, at least about 11 ng/mL, at least about 12
ng/mL, at least about 13 ng/mL, at least about 14 ng/mL, at least
about 15 ng/mL, at least about 16 ng/mL, at least about 17 ng/mL,
at least about 18 ng/mL, at least about 19 ng/mL, at least about 20
ng/mL, at least about 21 ng/mL, at least about 22 ng/mL, at least
about 23 ng/mL, at least about 24 ng/mL, at least about 25 ng/mL,
at least about 26 ng/mL, at least about 27 ng/mL, at least about 28
ng/mL, at least about 29 ng/mL, or at least about 30 ng/mL,
[0090] In one embodiment, the C.sub.max of betahistine in human
plasma concentration after single dose administration of the
intranasal pharmaceutical composition of the present disclosure is
at least about 3.5 ng/mL. In one embodiment, the C.sub.max of
betahistine in human plasma concentration is measured after single
dose administration of the intranasal pharmaceutical composition
comprising about 1 mg to about 200 mg of betahistine or a
pharmaceutically acceptable salt. In one embodiment, the C.sub.max
is measured after a single intranasal dose administration of about
5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about
11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16
mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21
mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26
mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31
mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36
mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41
mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46
mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51
mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56
mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg, about 61
mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg, about 66
mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg, about 71
mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about 76
mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81
mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86
mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about 91
mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96
mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg, of
betahistine or a pharmaceutically acceptable salt.
[0091] In one embodiment, the C.sub.max is measured after a single
intranasal dose administration of about 20 mg or about 40 mg of
betahistine or a pharmaceutically acceptable salt. In another
embodiment, the C.sub.max is measured after a single intranasal
dose administration of about 5 mg, about 10 mg, about 15 mg, about
20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70
mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about
200 mg of betahistine or a pharmaceutically acceptable salt.
[0092] In one embodiment, the intranasal pharmaceutical composition
of the present disclosure demonstrates good tolerance and a
dose-dependent increase in betahistine plasma concentrations,
higher than what can be detected after oral betahistine
administration.
[0093] In one embodiment, the pharmaceutical composition of the
present disclosure provides a t.sub.max of betahistine in human
plasma concentration after single dose administration of the
pharmaceutical composition of the present disclosure. In one
embodiment, the t.sub.max of betahistine in human plasma
concentration after single dose administration of the
pharmaceutical composition of the present disclosure is about 0.05
h or greater, 0.06 h or greater, 0.07 h or greater, about 0.08 h or
greater, about 0.09 h or greater, about 0.1 h or greater, about
0.11 h or greater, about 0.12 h or greater, about 0.13 h or
greater, about 0.14 h or greater, about 0.15 h or greater, about
0.16 h or greater, about 0.17 h or greater, about 0.18 h or
greater, about 0.19 h or greater, about 0.2 h or greater, about
0.25 h or greater, or about 0.3 h or greater. In one embodiment,
the t.sub.max is measured after a single dose administration of
about 1 mg to about 250 mg of betahistine or a pharmaceutically
acceptable salt. In one embodiment, the t.sub.max is measured after
a single dose of about 5 mg, about 10 mg, about 20 mg, about 30 mg,
about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg,
about 90 mg, about 100 mg, about 150 mg, or about 200 mg of
betahistine or a pharmaceutically acceptable salt.
[0094] In one embodiment, the t.sub.max of betahistine in human
plasma concentration after single dose administration of the
intranasal pharmaceutical composition of the present disclosure is
about 0.05 h or greater, 0.06 h or greater, 0.07 h or greater,
about 0.08 h or greater, about 0.09 h or greater, about 0.1 h or
greater, about 0.11 h or greater, about 0.12 h or greater, about
0.13 h or greater, about 0.14 h or greater, about 0.15 h or
greater, about 0.16 h or greater, about 0.17 h or greater, about
0.18 h or greater, about 0.19 h or greater, about 0.2 h or greater,
about 0.25 h or greater, or about 0.3 h or greater. In one
embodiment, the t.sub.max of betahistine in human plasma
concentration after single dose administration of the intranasal
pharmaceutical composition of the present disclosure is about 0.09
h or greater, about 0.1 h or greater, about 0.11 h or greater, or
about 0.12 h or greater. In one embodiment, the t.sub.max of
betahistine in human plasma concentration is determined after
single dose administration of the intranasal pharmaceutical
composition comprising about 1 mg to about 200 mg of betahistine or
a pharmaceutically acceptable salt. In one embodiment, the
t.sub.max is determined after a single intranasal dose
administration of about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9
mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14
mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19
mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24
mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29
mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34
mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39
mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44
mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49
mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54
mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59
mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64
mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about 69
mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74
mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79
mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg, about 84
mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg, about 89
mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg, about 94
mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg, about 99
mg, or about 100 mg, of betahistine or a pharmaceutically
acceptable salt.
[0095] In one embodiment, the t.sub.max is determined after a
single intranasal dose administration of about 20 mg or about 40 mg
of betahistine or a pharmaceutically acceptable salt. In another
embodiment, the t.sub.max is determined after a single intranasal
dose administration of about 5 mg, about 10 mg, about 15 mg, about
20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70
mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about
200 mg of betahistine or a pharmaceutically acceptable salt.
[0096] In one embodiment, the pharmaceutical composition of the
present disclosure provides an AUC.sub.0-last of betahistine in
human plasma concentration after single dose administration of the
pharmaceutical composition of the present disclosure of at least
about 50 hr*pg/mL, at least about 100 hr*pg/mL, at least about 200
hr*pg/mL, at least about 250 hr*pg/mL, at least about 300 hr*pg/mL,
at least about 400 hr*pg/mL, at least about 500 hr*pg/mL, at least
about 600 hr*pg/mL, at least about 700 hr*pg/mL, at least about 800
hr*pg/mL, at least about 900 hr*pg/mL, at least about 1000
hr*pg/mL, at least about 1100 hr*pg/mL, at least about 1200
hr*pg/mL, at least about 1300 hr*pg/mL, at least about 1400
hr*pg/mL, at least about 1500 hr*pg/mL, at least about 1600
hr*pg/mL, at least about 1700 hr*pg/mL, at least about 1800
hr*pg/mL, at least about 1900 hr*pg/mL, at least about 2000
hr*pg/mL, at least about 2100 hr*pg/mL, at least about 2200
hr*pg/mL, at least about 2300 hr*pg/mL, at least about 2400
hr*pg/mL, at least about 2500 hr*pg/mL, at least about 2600
hr*pg/mL, at least about 2700 hr*pg/mL, at least about 2800
hr*pg/mL, at least about 2900 hr*pg/mL, at least about 3000
hr*pg/mL, at least about 3100 hr*pg/mL, at least about 3200
hr*pg/mL, at least about 3300 hr*pg/mL, at least about 3400
hr*pg/mL, or at least about 3500 hr*pg/mL. In one embodiment, the
AUC.sub.0-last is measured after a single dose administration of
about 1 mg to about 250 mg of betahistine or a pharmaceutically
acceptable salt.
[0097] In one embodiment, the AUC.sub.0-last of betahistine in
human plasma concentration after single dose administration of the
intranasal pharmaceutical composition of the present disclosure is
at least about 0.05 hr*ng/mL, at least about 0.1 hr*ng/mL, at least
about 0.2 hr*ng/mL, at least about 0.25 hr*ng/mL, at least about
0.3 hr*ng/mL, at least about 0.4 hr*ng/mL, at least about 0.5
hr*ng/mL, at least about 0.6 hr*ng/mL, at least about 0.7 hr*ng/mL,
at least about 0.8 hr*ng/mL, at least about 0.9 hr*ng/mL, at least
about 1.0 hr*ng/mL, at least about 1.1 hr*ng/mL, at least about 1.2
hr*ng/mL, at least about 1.3 hr*ng/mL, at least about 1.4 hr*ng/mL,
at least about 1.5 hr*ng/mL, at least about 1.6 hr*ng/mL, at least
about 1.7 hr*ng/mL, at least about 1.8 hr*ng/mL, at least about 1.9
hr*ng/mL, at least about 2.0 hr*ng/mL, at least about 2.1 hr*ng/mL,
at least about 2.2 hr*ng/mL, at least about 2.3 hr*ng/mL, at least
about 2.4 hr*ng/mL, at least about 2.5 hr*ng/mL, at least about 2.6
hr*ng/mL, at least about 2.7 hr*ng/mL, at least about 2.8 hr*ng/mL,
at least about 2.9 hr*ng/mL, at least about 3.0 hr*ng/mL, at least
about 3.1 hr*ng/mL, at least about 3.2 hr*ng/mL, at least about 3.3
hr*ng/mL, at least about 3.4 hr*ng/mL, at least about 3.5 hr*ng/mL,
at least about 3.6 hr*ng/mL, at least about 3.7 hr*ng/mL, at least
about 3.8 hr*ng/mL, at least about 3.9 hr*ng/mL, at least about 4.0
hr*ng/mL. In one embodiment, the AUC.sub.0-last of betahistine in
human plasma concentration after single dose administration of the
intranasal pharmaceutical composition of the present disclosure is
at least about 1.5 hr*ng/mL or at least about 3.0 hr*ng/mL.
[0098] In one embodiment, the AUC.sub.0-last of betahistine in
human plasma concentration is determined after single dose
administration of the intranasal pharmaceutical composition
comprising about 1 mg to about 200 mg of betahistine or a
pharmaceutically acceptable salt. In one embodiment, the
AUC.sub.0-last is determined after a single intranasal dose of
about 5 mg, 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg,
about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg,
about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg,
about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg,
about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg,
about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg,
about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg,
about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg,
about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg,
about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg,
about 56 mg, about 57 mg, about 58 mg, about 59 mg, about 60 mg,
about 61 mg, about 62 mg, about 63 mg, about 64 mg, about 65 mg,
about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg,
about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg,
about 76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg,
about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg,
about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg,
about 91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg,
about 96 mg, about 97 mg, about 98 mg, about 99 mg, or about 100 mg
of betahistine or a pharmaceutically acceptable salt. In one
embodiment, the AUC.sub.0-last is determined after a single
intranasal dose administration of about 20 mg or about 40 mg of
betahistine or a pharmaceutically acceptable salt. In another
embodiment, the AUC.sub.0-last is determined after a single
intranasal dose administration of about 5 mg, about 10 mg, about 15
mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60
mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150
mg, or about 200 mg of betahistine or a pharmaceutically acceptable
salt.
[0099] In various embodiments, the AUC.sub.0-last ranges from about
80%-125% of about 210 pg*hr/mL for a 5 mg betahistine dose
administered intranasally; about 80%-125% of about 500 pg*hr/mL for
a 10 mg betahistine dose administered intranasally; about 80%-125%
of about 1600 pg*hr/mL for a 20 mg betahistine dose administered
intranasally; and about 80%-125% of about 3500 pg*hr/mL for a 40 mg
betahistine dose administered intranasally.
[0100] In some embodiments, the AUC.sub.0-last for a 5 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 200 pg*hr/mL, 300 pg*hr/mL, 400 pg*hr/mL,
500 pg*hr/mL, 600 pg*hr/mL, 700 pg*hr/mL, 800 pg*hr/mL, 900
pg*hr/mL, 1000 pg*hr/mL, 1100 pg*hr/mL, 1200 pg*hr/mL, 1300
pg*hr/mL, 1400 pg*hr/mL, or 1500 pg*hr/mL.
[0101] In some other embodiments, the AUC.sub.0-last for a 5 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 200 to about 500 pg*hr/mL, about 200 to
about 600 pg*hr/mL, about 300 to about 700 pg*hr/mL, about 400 to
about 800 pg*hr/mL, about 500 to about 1000 pg*hr/mL, about 600 to
about 1100 pg*hr/mL, about 750 to about 1250 pg*hr/mL, or about 800
to about 1400 pg*hr/mL.
[0102] In some embodiments, the AUC.sub.0-last for a 10 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 500 pg*hr/mL, 600 pg*hr/mL, 700 pg*hr/mL,
800 pg*hr/mL, 900 pg*hr/mL, 1000 pg*hr/mL, 1100 pg*hr/mL, 1200
pg*hr/mL, 1300 pg*hr/mL, 1400 pg*hr/mL, or 1500 pg*hr/mL.
[0103] In some other embodiments, the AUC.sub.0-last for a 10 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 400 to about 800 pg*hr/mL, about 500 to
about 800 pg*hr/mL, about 500 to about 900 pg*hr/mL, about 500 to
about 1000 pg*hr/mL, about 500 to about 1200 pg*hr/mL, about 600 to
about 1000 pg*hr/mL, about 600 to about 1100 pg*hr/mL, about 600 to
about 1200 pg*hr/mL, about 700 to about 1100 pg*hr/mL, about 700 to
about 1200 pg*hr/mL, about 800 to about 1300 pg*hr/mL, about 800 to
about 1200 pg*hr/mL, or about 900 to about 1200 pg*hr/mL.
[0104] In some embodiments, the AUC.sub.0-last for a 20 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 1500 pg*hr/mL, 1600 pg*hr/mL, 1700 pg*hr/mL,
1800 pg*hr/mL, 1900 pg*hr/mL, 2000 pg*hr/mL, 2100 pg*hr/mL, 2200
pg*hr/mL, 2300 pg*hr/mL, 2400 pg*hr/mL, 2500 pg*hr/mL, 2600
pg*hr/mL, 2700 pg*hr/mL, 2800 pg*hr/mL, 2900 pg*hr/mL, or 3000
pg*hr/mL.
[0105] In some other embodiments, the AUC.sub.0-last for a 20 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 1500 to about 2000 pg*hr/mL, about 1500 to
about 2200 pg*hr/mL, about 1600 to about 2100 pg*hr/mL, about 1700
to about 2200 pg*hr/mL, about 1700 to about 2400 pg*hr/mL, about
1800 to about 2400 pg*hr/mL, about 1900 to about 2500 pg*hr/mL,
about 2000 to about 2500 pg*hr/mL, about 2100 to about 2700
pg*hr/mL, or about 2200 to about 2900 pg*hr/mL.
[0106] In some embodiments, the AUC.sub.0-last for a 40 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 3300 pg*hr/mL, 3400 pg*hr/mL, 3500 pg*hr/mL,
3600 pg*hr/mL, 3700 pg*hr/mL, 3800 pg*hr/mL, 3900 pg*hr/mL, 4000
pg*hr/mL, 4100 pg*hr/mL, 4250 pg*hr/mL, 4500 pg*hr/mL, 4750
pg*hr/mL, 5000 pg*hr/mL, 5250 pg*hr/mL, 5500 pg*hr/mL, 5750
pg*hr/mL, 6000 pg*hr/mL, 6250 pg*hr/mL, 6500 pg*hr/mL, or 7000
pg*hr/mL.
[0107] In some other embodiments, the AUC.sub.0-last for a 40 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 3300 to about 3800 pg*hr/mL, about 3300 to
about 4000 pg*hr/mL, about 3300 to about 4200 pg*hr/mL, about 3300
to about 4500 pg*hr/mL, about 3500 to about 4000 pg*hr/mL, about
3500 to about 4200 pg*hr/mL, about 3500 to about 4500 pg*hr/mL,
about 3750 to about 4250 pg*hr/mL, about 3750 to about 4500
pg*hr/mL, about 3750 to about 4750 pg*hr/mL, about 4000 to about
5000 pg*hr/mL, or about 4000 to about 5500 pg*hr/mL.
[0108] In some embodiments, the AUC.sub.0-last for a 60 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 5300 pg*hr/mL, 5400 pg*hr/mL, 5500 pg*hr/mL,
about 5750 pg*hr/mL, 6000 pg*hr/mL, 6250 pg*hr/mL, 6500 pg*hr/mL,
6750 pg*hr/mL, 7000 pg*hr/mL, 7250 pg*hr/mL, 7500 pg*hr/mL, 7750
pg*hr/mL, or about 8000 pg*hr/mL.
[0109] In some other embodiments, the AUC.sub.0-last for a 60 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 5300 to about 5800 pg*hr/mL, about 5400 to
about 5900 pg*hr/mL, about 5500 to about 6000 pg*hr/mL, about 5400
to about 6200 pg*hr/mL, about 5500 to about 6400 pg*hr/mL, about
5500 to about 6700 pg*hr/mL, about 5500 to about 6900 pg*hr/mL,
about 5700 to about 6300 pg*hr/mL, about 5700 to about 6500
pg*hr/mL, about 5700 to about 6700 pg*hr/mL, about 5900 to about
6500 pg*hr/mL, about 5900 to about 6700 pg*hr/mL, about 6000 to
about 7250 pg*hr/mL, about 6000 to about 7000 pg*hr/mL, about 6000
to about 7500 pg*hr/mL.
[0110] In some embodiments, the AUC.sub.0-last for a 80 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 7500 pg*hr/mL, 7750 pg*hr/mL, 8000 pg*hr/mL,
8250 pg*hr/mL, 8500 pg*hr/mL, 8750 pg*hr/mL, 9000 pg*hr/mL, 9250
pg*hr/mL, 9500 pg*hr/mL, 9750 pg*hr/mL, or 10000 pg*hr/mL.
[0111] In some other embodiments, the AUC.sub.0-last for a 80 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 7300 to about 8000 pg*hr/mL, about 7500 to
about 8200 pg*hr/mL, about 7500 to about 8000 pg*hr/mL, about 7500
to about 8500 pg*hr/mL, about 7750 to about 8500 pg*hr/mL, about
7750 to about 8750 pg*hr/mL, about 8000 to about 8500 pg*hr/mL,
about 8000 to about 8750 pg*hr/mL, about 8000 to about 9000
pg*hr/mL, about 8250 to about 9000 pg*hr/mL, about 8250 to about
8750 pg*hr/mL, about 8250 to about 9250 pg*hr/mL, about 8500 to
about 9500 pg*hr/mL, or about 8500 to about 9000 pg*hr/mL.
[0112] In one embodiment, the pharmaceutical composition of the
present disclosure provides an AUC.sub.0-inf of betahistine in
human plasma concentration after single dose administration of the
pharmaceutical composition of the present disclosure of at least
about 100 hr*pg/mL, at least about 200 hr*pg/mL, at least about 250
hr*pg/mL, at least about 300 hr*pg/mL, at least about 400 hr*pg/mL,
at least about 500 hr*pg/mL, at least about 600 hr*pg/mL, at least
about 700 hr*pg/mL, at least about 800 hr*pg/mL, at least about 900
hr*pg/mL, at least about 1000 hr*pg/mL, at least about 1100
hr*pg/mL, at least about 1200 hr*pg/mL, at least about 1300
hr*pg/mL, at least about 1400 hr*pg/mL, at least about 1500
hr*pg/mL, at least about 1600 hr*pg/mL, at least about 1700
hr*pg/mL, at least about 1800 hr*pg/mL, at least about 1900
hr*pg/mL, at least about 2000 hr*pg/mL, at least about 2100
hr*pg/mL, at least about 2200 hr*pg/mL, at least about 2300
hr*pg/mL, at least about 2400 hr*pg/mL, at least about 2500
hr*pg/mL, at least about 2600 hr*pg/mL, at least about 2700
hr*pg/mL, at least about 2800 hr*pg/mL, at least about 2900
hr*pg/mL, at least about 3000 hr*pg/mL, at least about 3100
hr*pg/mL, at least about 3200 hr*pg/mL, at least about 3300
hr*pg/mL, at least about 3400 hr*pg/mL, or at least about 3500
hr*pg/mL. In one embodiment, the AUC.sub.0-inf is measured after a
single dose administration of about 1 mg to about 250 mg of
betahistine or a pharmaceutically acceptable salt.
[0113] In one embodiment, the AUC.sub.0-inf of betahistine in human
plasma concentration after single dose administration of the
intranasal pharmaceutical composition of the present disclosure is
at least about 0.1 hr*ng/mL, at least about 0.2 hr*ng/mL, at least
about 0.25 hr*ng/mL, at least about 0.3 hr*ng/mL, at least about
0.4 hr*ng/mL, at least about 0.5 hr*ng/mL, at least about 0.6
hr*ng/mL, at least about 0.7 hr*ng/mL, at least about 0.8 hr*ng/mL,
at least about 0.9 hr*ng/mL, at least about 1.0 hr*ng/mL, at least
about 1.1 hr*ng/mL, at least about 1.2 hr*ng/mL, at least about 1.3
hr*ng/mL, at least about 1.4 hr*ng/mL, at least about 1.5 hr*ng/mL,
at least about 1.6 hr*ng/mL, at least about 1.7 hr*ng/mL, at least
about 1.8 hr*ng/mL, at least about 1.9 hr*ng/mL, at least about 2.0
hr*ng/mL, at least about 2.1 hr*ng/mL, at least about 2.2 hr*ng/mL,
at least about 2.3 hr*ng/mL, at least about 2.4 hr*ng/mL, at least
about 2.5 hr*ng/mL, at least about 2.6 hr*ng/mL, at least about 2.7
hr*ng/mL, at least about 2.8 hr*ng/mL, at least about 2.9 hr*ng/mL,
at least about 3.0 hr*ng/mL, at least about 3.1 hr*ng/mL, at least
about 3.2 hr*ng/mL, at least about 3.3 hr*ng/mL, at least about 3.4
hr*ng/mL, at least about 3.5 hr*ng/mL, at least about 3.6 hr*ng/mL,
at least about 3.7 hr*ng/mL, at least about 3.8 hr*ng/mL, at least
about 3.9 hr*ng/mL, at least about 4.0 hr*ng/mL. In one embodiment,
the AUC.sub.0-inf of betahistine in human plasma concentration
after single dose administration of the intranasal pharmaceutical
composition of the present disclosure is at least about 1.5
hr*ng/mL or at least about 3.0 hr*ng/mL.
[0114] In one embodiment, the AUC.sub.0-inf of betahistine in human
plasma concentration is determined after single dose administration
of the intranasal pharmaceutical composition comprising about 1 mg
to about 200 mg of betahistine or a pharmaceutically acceptable
salt. In one embodiment, the AUC.sub.0-inf is determined after a
single intranasal dose of about 5 mg, 6 mg, about 7 mg, about 8 mg,
about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg,
about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg,
about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg,
about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg,
about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg,
about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg,
about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg,
about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg,
about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg,
about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg,
about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg,
about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg,
about 69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg,
about 74 mg, about 75 mg, about 76 mg, about 77 mg, about 78 mg,
about 79 mg, about 80 mg, about 81 mg, about 82 mg, about 83 mg,
about 84 mg, about 85 mg, about 86 mg, about 87 mg, about 88 mg,
about 89 mg, about 90 mg, about 91 mg, about 92 mg, about 93 mg,
about 94 mg, about 95 mg, about 96 mg, about 97 mg, about 98 mg,
about 99 mg, or about 100 mg of betahistine or a pharmaceutically
acceptable salt. In one embodiment, AUC.sub.0-inf is determined
after a single intranasal dose administration of about 20 mg or
about 40 mg of betahistine or a pharmaceutically acceptable salt.
In another embodiment, the AUC.sub.0-inf is determined after a
single intranasal dose administration of about 5 mg, about 10 mg,
about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,
about 150 mg, or about 200 mg of betahistine or a pharmaceutically
acceptable salt.
[0115] In various embodiments, the AUC.sub.0-inf of betahistine
ranges from about 80%-125% of about 275 pg*hr/mL for a 5 mg
betahistine dose administered intranasally; about 80%-125% of about
700 pg*hr/mL for a 10 mg betahistine dose administered
intranasally; about 80%-125% of about 1630 pg*hr/mL for a 20 mg
betahistine dose administered intranasally; and about 80%-125% of
about 2940 pg*hr/mL for a 40 mg betahistine dose administered
intranasally.
[0116] In some embodiments, the AUC.sub.0-inf for a 5 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 250 pg*hr/mL, 275 pg*hr/mL, 300 pg*hr/mL,
350 pg*hr/mL, 400 pg*hr/mL, 450 pg*hr/mL, 500 pg*hr/mL, 600
pg*hr/mL, 700 pg*hr/mL, 800 pg*hr/mL, 900 pg*hr/mL, or 1000
pg*hr/mL.
[0117] In some other embodiments, the AUC.sub.0-inf for a 5 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 250 to about 350 pg*hr/mL, about 250 to
about 500 pg*hr/mL, about 275 to about 375 pg*hr/mL, about 275 to
about 475 pg*hr/mL, about 275 to about 575 pg*hr/mL, about 250 to
850 pg*hr/mL, about 300 to about 800 pg*hr/mL, about 300 to about
700 pg*hr/mL, about 400 to about 800 pg*hr/mL, about 500 to about
1000 pg*hr/mL, about 750 to about 1250 pg*hr/mL, or about 750 to
about 1500 pg*hr/mL.
[0118] In some embodiments, the AUC.sub.0-inf for a 10 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 650 pg*hr/mL, about 700 pg*hr/mL, about 800
pg*hr/mL, about 900 pg*hr/mL, about 1000 pg*hr/mL, about 1250
pg*hr/mL, about about 1500 pg*hr/mL, about 1750 pg*hr/mL, or about
2000 pg*hr/mL.
[0119] In some other embodiments, the AUC.sub.0-inf for a 10 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 650 to about 1000 pg*hr/mL, about 650 to
about 1250 pg*hr/mL, about 700 to about 1400 pg*hr/mL, about 700 to
about 1200 pg*hr/mL, about 700 to 1000 pg*hr/mL, about 800 to about
1200 pg*hr/mL, about 800 to about 1400 pg*hr/mL, about 800 to about
1600 pg*hr/mL, about 1000 to about 1500 pg*hr/mL, or about 1000 to
about 2000 pg*hr/mL.
[0120] In some embodiments, the AUC.sub.0-inf for a 20 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 1600 pg*hr/mL, about 1700 pg*hr/mL, about
1800 pg*hr/mL, about 1900 pg*hr/mL, about 2000 pg*hr/mL, about 2250
pg*hr/mL, about 2500 pg*hr/mL, about 2750 pg*hr/mL, about 3000
pg*hr/mL, or about 3500 pg*hr/mL.
[0121] In some other embodiments, the AUC.sub.0-inf for a 20 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 1600 to about 2000 pg*hr/mL, about 1600 to
about 2200 pg*hr/mL, about 1600 to about 2400 pg*hr/mL, about 1600
to about 2600 pg*hr/mL, about 1800 to about 2400 pg*hr/mL, about
1800 to about 2600 pg*hr/mL, about 1800 to about 2800 pg*hr/mL,
about 2000 to about 3000 pg*hr/mL, about 2000 to about 2500
pg*hr/mL, about 2000 to about 2800 pg*hr/mL, about 2250 to about
3250 pg*hr/mL, about 2250 to about 3000 pg*hr/mL, about 2500 to
about 3500 pg*hr/mL, or about 2500 to about 3000 pg*hr/mL.
[0122] In some embodiments, the AUC.sub.0-inf for a 40 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 2800 pg*hr/mL, about 2900 pg*hr/mL, about
2950 pg*hr/mL, about 3000 pg*hr/mL, about 3100 pg*hr/mL, about 3200
pg*hr/mL, about 3300 pg*hr/mL, about 3400 pg*hr/mL, about 3500
pg*hr/mL, about 3600 pg*hr/mL, about 3700 pg*hr/mL, about 3800
pg*hr/mL, about 3900 pg*hr/mL, about 4000 pg*hr/mL, about 4250
pg*hr/mL, about 4500 pg*hr/mL, about 4750 pg*hr/mL, about 5000
pg*hr/mL, about 5250 pg*hr/mL, about 5500 pg*hr/mL, about 5750
pg*hr/mL, or about 6000 pg*hr/mL.
[0123] In some other embodiments, the AUC.sub.0-inf for a 40 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 2800 to about 3300 pg*hr/mL, about 2800 to
about 3500 pg*hr/mL, about 2800 to about 3800 pg*hr/mL, about 3000
to about 3500 pg*hr/mL, about 3500 to about 3750 pg*hr/mL, about
3000 to about 4000 pg*hr/mL, about 3250 to about 4250 pg*hr/mL,
about 3250 to about 4500 pg*hr/mL, about 3500 to about 4500
pg*hr/mL, about 3500 to about 4000 pg*hr/mL, about 3750 to about
4750 pg*hr/mL, about 3750 to about 4500 pg*hr/mL, about 4000 to
about 5000 pg*hr/mL, about 4500 to about 5500 pg*hr/mL, or about
5000 to about 6000 pg*hr/mL.
[0124] In some embodiments, the AUC.sub.0-inf for a 60 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 5300 pg*hr/mL, 5400 pg*hr/mL, 5500 pg*hr/mL,
about 5750 pg*hr/mL, 6000 pg*hr/mL, 6250 pg*hr/mL, 6500 pg*hr/mL,
6750 pg*hr/mL, 7000 pg*hr/mL, 7250 pg*hr/mL, 7500 pg*hr/mL, 7750
pg*hr/mL, or about 8000 pg*hr/mL.
[0125] In some other embodiments, the AUC.sub.0-inf for a 60 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 5300 to about 5800 pg*hr/mL, about 5400 to
about 5900 pg*hr/mL, about 5500 to about 6000 pg*hr/mL, about 5400
to about 6200 pg*hr/mL, about 5500 to about 6400 pg*hr/mL, about
5500 to about 6700 pg*hr/mL, about 5500 to about 6900 pg*hr/mL,
about 5700 to about 6300 pg*hr/mL, about 5700 to about 6500
pg*hr/mL, about 5700 to about 6700 pg*hr/mL, about 5900 to about
6500 pg*hr/mL, about 5900 to about 6700 pg*hr/mL, about 6000 to
about 7250 pg*hr/mL, about 6000 to about 7000 pg*hr/mL, about 6000
to about 7500 pg*hr/mL.
[0126] In some embodiments, the AUC.sub.0-inf for a 80 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 7500 pg*hr/mL, 7750 pg*hr/mL, 8000 pg*hr/mL,
8250 pg*hr/mL, 8500 pg*hr/mL, 8750 pg*hr/mL, 9000 pg*hr/mL, 9250
pg*hr/mL, 9500 pg*hr/mL, 9750 pg*hr/mL, or 10000 pg*hr/mL.
[0127] In some other embodiments, the AUC.sub.0-inf for a 80 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 7300 to about 8000 pg*hr/mL, about 7500 to
about 8200 pg*hr/mL, about 7500 to about 8000 pg*hr/mL, about 7500
to about 8500 pg*hr/mL, about 7750 to about 8500 pg*hr/mL, about
7750 to about 8750 pg*hr/mL, about 8000 to about 8500 pg*hr/mL,
about 8000 to about 8750 pg*hr/mL, about 8000 to about 9000
pg*hr/mL, about 8250 to about 9000 pg*hr/mL, about 8250 to about
8750 pg*hr/mL, about 8250 to about 9250 pg*hr/mL, about 8500 to
about 9500 pg*hr/mL, or about 8500 to about 9000 pg*hr/mL.
[0128] In one embodiment, absolute bioavailability (% F) of
betahistine administered intranasally is about 10%, 15%, 20%, 25%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.
In one embodiment, absolute bioavailability (% F) of betahistine
administered intranasally is about 30-80%, about 25-75%, about
20-60%, about 10-50%, about 30-60%, about 40-60%, about 40-70%,
about 40-80%, or about 50-80%.
[0129] In one embodiment, the relative bioavailability (F.sub.rel)
for 5 mg betahistine administered intranasally is about 10, 11, 12,
13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 times the
oral bioavailability. In one embodiment, the relative
bioavailability for 10 mg betahistine administered intranasally is
about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29
times the oral bioavailability. In one embodiment, the relative
bioavailability for 20 mg betahistine administered intranasally is
about 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,
or 42 times the oral bioavailability. In one embodiment, the
relative bioavailability for 40 mg betahistine administered
intranasally is about 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46
times the oral bioavailability. In one embodiment, the relative
bioavailability for 60 mg betahistine administered intranasally is
about 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,
60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 times the oral
bioavailability. In one embodiment, the relative bioavailability
for 80 mg betahistine administered intranasally is about 50, 51,
52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,
69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 times the oral
bioavailability. In one embodiment, the relative bioavailability
for 100 mg betahistine administered intranasally is about 50, 51,
52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,
69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,
86, 87, 88, 89, or 90 times the oral bioavailability.
[0130] In one embodiment, the relative bioavailability for
betahistine administered intranasally is up to about 10-25, about
15-30, about 20-40, about 20-30, about 20-50, about 25-40, about
25-45, about 25-50, about 15-45, about 30-60 times the oral
bioavailability.
[0131] In one embodiment, the t.sub.1/2 (apparent half-life) of
betahistine determined based on a single dose administration of the
pharmaceutical composition of the present disclosure is about 0.07
h or greater, about 0.08 h or greater, about 0.09 h or greater,
about 0.1 h or greater, about 0.2 h or greater, about 0.3 h or
greater, about 0.4 h or greater, about 0.5 h or greater, about 0.6
h or greater, about 0.6 h or greater, about 0.8 h or greater, about
0.9 h or greater, or about 1.0 h or greater. In one embodiment, the
t.sub.1/2 is determined based on a single dose administration of
about 1 mg to about 250 mg of betahistine or a pharmaceutically
acceptable salt. In one embodiment, the t.sub.1/2 is determined
based on a single dose administration of about 5 mg, about 10 mg,
about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg,
about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg,
or about 200 mg of betahistine or a pharmaceutically acceptable
salt.
[0132] In one embodiment, the t.sub.1/2 (apparent half-life) of
betahistine determined based on a single dose administration of the
intranasal pharmaceutical composition of the present disclosure is
about 0.07 h or greater, about 0.08 h or greater, about 0.09 h or
greater, about 0.1 h or greater, about 0.2 h or greater, about 0.3
h or greater, about 0.4 h or greater, about 0.5 h or greater, about
0.6 h or greater, about 0.6 h or greater, about 0.8 h or greater,
about 0.9 h or greater, or about 1.0 h or greater. In one
embodiment, the t.sub.1/2 of betahistine determined based on a
single dose administration of the intranasal pharmaceutical
composition of the present disclosure is about 0.4 h or greater or
about 0.8 h or greater. In one embodiment, the t.sub.1/2 of
betahistine determined based on a single dose of the intranasal
pharmaceutical composition of the present disclosure is about 0.5 h
or about 0.9 h.
[0133] In one embodiment, the t.sub.1/2 is determined based on a
single intranasal dose administration of about 1 mg to about 200 mg
of betahistine or a pharmaceutically acceptable salt. In one
embodiment, the t.sub.1/2 is determined based on a single
intranasal dose administration of about 5 mg, 6 mg, about 7 mg,
about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg,
about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg,
about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg,
about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg,
about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg,
about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg,
about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg,
about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg,
about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg,
about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg,
about 58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg,
about 63 mg, about 64 mg, about 65 mg, about 66 mg, about 67 mg,
about 68 mg, about 69 mg, about 70 mg, about 71 mg, about 72 mg,
about 73 mg, about 74 mg, about 75 mg, about 76 mg, about 77 mg,
about 78 mg, about 79 mg, about 80 mg, about 81 mg, about 82 mg,
about 83 mg, about 84 mg, about 85 mg, about 86 mg, about 87 mg,
about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg,
about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg,
about 98 mg, about 99 mg, or about 100 mg of betahistine or a
pharmaceutically acceptable salt. In one embodiment, the t.sub.1/2
is determined based on a single intranasal dose administration of
about 20 mg or about 40 mg of betahistine or a pharmaceutically
acceptable salt. In another embodiment, the t.sub.1/2 is determined
based on a single intranasal dose administration of about 5 mg,
about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg,
about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,
about 100 mg, about 150 mg, or about 200 mg of betahistine or a
pharmaceutically acceptable salt.
[0134] In one embodiment, the pharmaceutical composition of the
present disclosure provides a detectable C.sub.max of 2-PAA
(2-pyridylacetic acid) in human plasma concentration after single
dose administration of the pharmaceutical composition of the
present disclosure. In one embodiment, the C.sub.max of 2-PAA in
human plasma concentration after single dose administration of the
pharmaceutical composition of the present disclosure is at least
about 15 ng/mL or at least about 50 ng/mL. In one embodiment, the
C.sub.max of 2-PAA is measured after a single dose administration
of about 1 mg to about 250 mg of betahistine or a pharmaceutically
acceptable salt. In one embodiment, the C.sub.max of 2-PAA is
measured after a single dose administration of about 5 mg, about 10
mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60
mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150
mg, or about 200 mg of betahistine or a pharmaceutically acceptable
salt. In other embodiments, the C.sub.max of 2-PAA for a 5 mg
betahistine dose, administered intranasally, ranges from about 80%
to about 125% of about 65 ng/ml; about 80% to about 125% of about
150 ng/ml for a 10 mg betahistine dose, administered intranasally;
about 80% to about 125% of about 370 ng/ml for a 20 mg betahistine
dose, administered intranasally; and about 80% to about 125% of
about 520 ng/ml for a 40 mg betahistine days, administered
intranasally. In other embodiments, the C.sub.max of 2-PAA for a 5
mg betahistine dose, administered intranasally, ranges from about
80% to about 125% of about 16 to about 95 ng/ml; about 80% to about
125% of about 115 ng/ml to about 175 ng/ml for a 10 mg betahistine
dose, administered intranasally; about 80% to about 125% of about
250 to about 430 g/ml for a 20 mg betahistine dose, administered
intranasally; and about 80% to about 125% of about 290 to about 690
ng/ml for a 40 mg betahistine days, administered intranasally.
[0135] In one embodiment, the C.sub.max of 2-PAA in human plasma
concentration after single dose administration of the intranasal
pharmaceutical composition of the present disclosure is at least
about 15 ng/mL or at least about 50 ng/mL. In one embodiment, the
C.sub.max of 2-PAA in human plasma concentration after single dose
administration of the intranasal pharmaceutical composition of the
present disclosure is at least about 10 ng/mL, at least about 15
ng/mL, at least about 20 ng/mL, at least about 25 ng/mL, at least
about 30 ng/mL, at least about 35 ng/mL, at least about 40 ng/mL,
at least about 45 ng/mL, at least about 50 ng/mL, at least about 55
ng/mL, at least about 60 ng/mL, at least about 65 ng/mL, at least
about 70 ng/mL, at least about 75 ng/mL, at least about 80 ng/mL,
at least about 85 ng/mL, at least about 90 ng/mL, at least about 95
ng/mL, at least about 100 ng/mL, at least about 150 ng/mL, at least
about 200 ng/mL, at least about 250 ng/mL, at least about 300
ng/mL, at least about 400 ng/mL, at least about 450 ng/mL, at least
about 500 ng/mL, or at least about 550 ng/mL.
[0136] In one embodiment, the C.sub.max of 2-PAA in human plasma
concentration after single dose administration of the intranasal
pharmaceutical composition of the present disclosure is at least
about 60 ng/mL. In one embodiment, the C.sub.max of 2-PAA in human
plasma concentration is measured after single dose administration
of the intranasal pharmaceutical composition comprising about 1 mg
to about 200 mg of betahistine or a pharmaceutically acceptable
salt. In one embodiment, the C.sub.max of 2-PAA is measured after a
single intranasal dose administration of about 5 mg to about 100 mg
of betahistine or a pharmaceutically acceptable salt. In one
embodiment, the C.sub.max of 2-PAA is measured after a single
intranasal dose administration of about 20 mg or about 40 mg of
betahistine or a pharmaceutically acceptable salt. In another
embodiment, the C.sub.max of 2-PAA is measured after a single
intranasal dose administration of about 5 mg, about 10 mg, about 15
mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60
mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150
mg, or about 200 mg of betahistine or a pharmaceutically acceptable
salt.
[0137] In one embodiment, the pharmaceutical composition of the
present disclosure provides a t.sub.max of 2-PAA in human plasma
concentration after single dose administration of the
pharmaceutical composition of the present disclosure. In one
embodiment, the t.sub.max of 2-PAA in human plasma concentration
after single dose administration of the pharmaceutical composition
of the present disclosure is about 0.6 h or greater, about 0.7 h or
greater, about 0.8 h or greater, about 0.9 h or greater, about 1 h
or greater, about 1.1 h or greater, about 1.2 h or greater, about
1.25 h or greater, about 1.3 h or greater, about 1.4 h or greater,
or about 1.5 h or greater. In one embodiment, the t.sub.max is
measured after a single dose administration of about 1 mg to about
250 mg of betahistine or a pharmaceutically acceptable salt. In one
embodiment, the t.sub.max is measured after a single dose of about
5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50
mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100
mg, about 150 mg, or about 200 mg of betahistine or a
pharmaceutically acceptable salt.
[0138] In one embodiment, the t.sub.max of 2-PAA in human plasma
concentration after single dose administration of the intranasal
pharmaceutical composition of the present disclosure is about 1.0
h. In one embodiment, the t.sub.max of 2-PAA in human plasma
concentration after single dose administration of the intranasal
pharmaceutical composition of the present disclosure is about 0.9 h
or greater, about 1.0 h or greater, about 1.1 h or greater, or
about 1.2 h or greater. In one embodiment, the t.sub.max of 2-PAA
in human plasma concentration is determined after single dose
administration of the intranasal pharmaceutical composition
comprising about 1 mg to about 200 mg of betahistine or a
pharmaceutically acceptable salt. In one embodiment, the t.sub.max
of 2-PAA is determined after a single intranasal dose
administration of about 5 mg to about 100 mg, of betahistine or a
pharmaceutically acceptable salt. In one embodiment, the t.sub.max
of 2-PAA is determined after a single intranasal dose
administration of about 20 mg or about 40 mg of betahistine or a
pharmaceutically acceptable salt. In another embodiment, the
t.sub.max of 2-PAA is determined after a single intranasal dose
administration of about 5 mg, about 10 mg, about 15 mg, about 20
mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70
mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, or about
200 mg of betahistine or a pharmaceutically acceptable salt.
[0139] In one embodiment, the pharmaceutical composition of the
present disclosure provides an AUC.sub.0-last of 2-PAA in human
plasma concentration after single dose administration of the
pharmaceutical composition of the present disclosure of at least
about 100 hr*ng/mL, at least about 200 hr*ng/mL, at least about 250
hr*ng/mL, at least about 300 hr*ng/mL, at least about 400 hr*ng/mL,
at least about 500 hr*ng/mL, at least about 600 hr*ng/mL, at least
about 700 hr*ng/mL, at least about 800 hr*ng/mL, at least about 900
hr*ng/mL, at least about 1000 hr*ng/mL, at least about 1100
hr*ng/mL, at least about 1200 hr*ng/mL, at least about 1300
hr*ng/mL, at least about 1400 hr*ng/mL, at least about 1500
hr*ng/mL, at least about 1600 hr*ng/mL, at least about 1700
hr*ng/mL, at least about 1800 hr*ng/mL, at least about 1900
hr*ng/mL, at least about 2000 hr*ng/mL, at least about 2100
hr*ng/mL, at least about 2200 hr*ng/mL, at least about 2300
hr*ng/mL, at least about 2400 hr*ng/mL, at least about 2500
hr*ng/mL, at least about 2600 hr*ng/mL, at least about 2700
hr*ng/mL, at least about 2800 hr*ng/mL, at least about 2900
hr*ng/mL, or at least about 3000 hr*ng/mL, at least about 3100
hr*ng/mL, at least about 3200 hr*ng/mL, at least about 3300
hr*ng/mL, at least about 3400 hr*ng/mL, or at least about 3500
hr*ng/mL. In one embodiment, the AUC.sub.0-last of 2-PAA is
measured after a single dose administration of about 1 mg to about
200 mg of betahistine or a pharmaceutically acceptable salt.
[0140] In one embodiment, the AUC.sub.0-last of 2-PAA in human
plasma concentration is determined after single dose administration
of the intranasal pharmaceutical composition comprising about 1 mg
to about 200 mg of betahistine or a pharmaceutically acceptable
salt. In one embodiment, the AUC.sub.0-last of 2-PAA is determined
after a single intranasal dose of about 5 mg to about 100 mg of
betahistine or a pharmaceutically acceptable salt. In one
embodiment, the AUC.sub.0-last of 2-PAA is determined after a
single intranasal dose administration of about 20 mg or about 40 mg
of betahistine or a pharmaceutically acceptable salt. In another
embodiment, the AUC.sub.0-last of 2-PAA is determined after a
single intranasal dose administration of about 5 mg, about 10 mg,
about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg,
about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,
about 150 mg, or about 200 mg of betahistine or a pharmaceutically
acceptable salt.
[0141] In various embodiments, the AUC.sub.0-last of 2-PAA ranges
from about 80%-125% of about 390 nghr/mL for a 5 mg betahistine
dose administered intranasally; about 80%-125% of about 730 nghr/mL
for a 10 mg betahistine dose administered intranasally; about
80%-125% of about 2000 nghr/mL for a 20 mg betahistine dose
administered intranasally; and about 80%-125% of about 2800 nghr/mL
for a 40 mg betahistine dose administered intranasally.
[0142] In one embodiment, the pharmaceutical composition of the
present disclosure provides an AUC.sub.0-inf 2-PAA in human plasma
concentration after single dose administration of the
pharmaceutical composition of the present disclosure of at least
about 100 hr*ng/mL, at least about 200 hr*ng/mL, at least about 250
hr*ng/mL, at least about 300 hr*ng/mL, at least about 400 hr*ng/mL,
at least about 500 hr*ng/mL, at least about 600 hr*ng/mL, at least
about 700 hr*ng/mL, at least about 800 hr*ng/mL, at least about 900
hr*ng/mL, at least about 1000 hr*ng/mL, at least about 1100
hr*ng/mL, at least about 1200 hr*ng/mL, at least about 1300
hr*ng/mL, at least about 1400 hr*ng/mL, at least about 1500
hr*ng/mL, at least about 1600 hr*ng/mL, at least about 1700
hr*ng/mL, at least about 1800 hr*ng/mL, at least about 1900
hr*ng/mL, at least about 2000 hr*ng/mL, at least about 2100
hr*ng/mL, at least about 2200 hr*ng/mL, at least about 2300
hr*ng/mL, at least about 2400 hr*ng/mL, at least about 2500
hr*ng/mL, at least about 2600 hr*ng/mL, at least about 2700
hr*ng/mL, at least about 2800 hr*ng/mL, at least about 2900
hr*ng/mL, at least about 3000 hr*ng/mL, at least about 3100
hr*ng/mL, at least about 3200 hr*ng/mL, at least about 3300
hr*ng/mL, at least about 3400 hr*ng/mL, or at least about 3500
hr*ng/mL. In one embodiment, the AUC.sub.0-inf of 2-PAA is measured
after a single dose administration of about 1 mg to about 200 mg of
betahistine or a pharmaceutically acceptable salt.
[0143] In one embodiment, the AUC.sub.0-inf of 2-PAA in human
plasma concentration is determined after single dose administration
of the intranasal pharmaceutical composition comprising about 1 mg
to about 200 mg of betahistine or a pharmaceutically acceptable
salt. In one embodiment, the AUC.sub.0-inf of 2-PAA is determined
after a single intranasal dose of about 5 mg to about 100 mg of
betahistine or a pharmaceutically acceptable salt. In one
embodiment, the AUC.sub.0-inf of 2-PAA is determined after a single
intranasal dose administration of about 20 mg or about 40 mg of
betahistine or a pharmaceutically acceptable salt. In another
embodiment, the AUC.sub.0-inf of 2-PAA is determined after a single
intranasal dose administration of about 5 mg, about 10 mg, about 15
mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60
mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150
mg, or about 200 mg of betahistine or a pharmaceutically acceptable
salt.
[0144] In various embodiments, the AUC.sub.0-inf of 2-PAA ranges
from about 80%-125% of about 430 nghr/mL for a 5 mg betahistine
dose administered intranasally; about 80%-125% of about 760 nghr/mL
for a 10 mg betahistine dose administered intranasally; about
80%-125% of about 2000 nghr/mL for a 20 mg betahistine dose
administered intranasally; and about 80%-125% of about 2900 nghr/mL
for a 40 mg betahistine dose administered intranasally.
[0145] In one embodiment, the t.sub.1/2 (apparent half-life) of
2-PAA determined based on a single dose administration of the
pharmaceutical composition of the present disclosure is about 2.5 h
or greater, about 2.6 h or greater, about 2.7 h or greater, about
2.8 h or greater, about 2.9 h or greater, about 3.0 h or greater,
about 3.1 h or greater, about 3.2 h or greater, about 3.3 h or
greater, about 3.4 h or greater, about 3.5 h or greater, about 3.6
h or greater, about 3.7 h or greater, about 3.8 h or greater, about
3.9 h or greater, about 4.0 h or greater, about 4.1 h or greater,
about 4.2 h or greater, about 4.3 h or greater, about 4.4 h or
greater, or about 4.5 h or greater. In one embodiment, the
t.sub.1/2 of 2-PAA is determined based on a single dose
administration of about 1 mg to about 200 mg of betahistine or a
pharmaceutically acceptable salt. In one embodiment, the t.sub.1/2
is of 2-PAA determined based on a single dose administration of
about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg,
about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg,
about 100 mg, about 150 mg, or about 200 mg of betahistine or a
pharmaceutically acceptable salt.
[0146] In one embodiment, the pharmaceutical composition of the
present disclosure can be useful in methods for use in treatment or
prophylaxis of vestibular disorders. In another embodiment, the
pharmaceutical composition of the present disclosure can be useful
in methods for use in treatment or prophylaxis of neurotological
disorders. In some embodiments, the pharmaceutical composition of
the present disclosure can be useful in methods for use in
treatment or prophylaxis of otological and/or neurological
disorders.
[0147] In one embodiment, the pharmaceutical composition of the
present disclosure can be useful in methods for use in the
treatment or prophylaxis of inner ear dysfunction or inner ear
disorder. In one embodiment, inner ear disorders include tinnitus,
vestibular vertigo, Meniere's disease, inner ear inflammation or
infection, autoimmune ear disorder, or hearing loss. In one
embodiment, the pharmaceutical composition of the present
disclosure can be useful in methods for use in treatment or
prophylaxis of tinnitus, vestibular vertigo, Meniere's disease, and
hearing loss. In one embodiment, the pharmaceutical composition of
the present disclosure can be useful for treating vestibular
vertigo. In another embodiment, the pharmaceutical composition of
the present disclosure can be useful for treating Meniere's
disease. In one embodiment, vestibular vertigo can include benign
paroxysmal positional vertigo, vestibular neuritis and other
peripheral vestibular vertigo.
[0148] In one embodiment, the pharmaceutical composition of the
present disclosure can be useful in methods for use in treatment or
prophylaxis or prevention of vertigo, vestibular vertigo, and/or
vertigo attacks. In another embodiment, the pharmaceutical
composition of the present disclosure can be useful for reducing or
reducing the symptoms of vertigo, vestibular vertigo, and/or
vertigo attacks.
[0149] In one embodiment, the pharmaceutical composition of the
present disclosure can be useful in methods for use in the
treatment or prophylaxis of Eustachian tube dysfunction.
[0150] In one embodiment, the pharmaceutical composition of the
present disclosure can be useful for treating or alleviating
symptoms of inner ear disorder. In one embodiment, inner ear
dysfunction and/or symptoms of inner ear disorder includes hearing
loss (including acute hearing loss), tinnitus, nausea and
dizziness. In one embodiment, the pharmaceutical composition of the
present disclosure can be useful for treating hearing loss. In
another embodiment, the pharmaceutical composition of the present
disclosure can be useful for treating acute hearing loss.
[0151] In one embodiment, the pharmaceutical composition of the
present disclosure can be useful as a part of a vestibular therapy.
In some embodiments, the vestibular therapy is vestibular
rehabilitation.
[0152] In one embodiment, the pharmaceutical composition of the
present disclosure can be useful for vestibular rehabilitation. In
one embodiment, the pharmaceutical composition of the present
disclosure can be useful for treating inner ear disorder or
symptoms thereof with or in addition to vestibular rehabilitation.
In one embodiment, the pharmaceutical composition of the present
disclosure can be useful for treating inner ear disorder or
symptoms thereof to facilitate vestibular rehabilitation.
[0153] Without being bound to any theory, betahistine or a
pharmaceutically acceptable salt thereof is believed to act as a
partial H1 receptor (H1R) agonist and/or reverse H3 receptor (H3R)
antagonist. H1R and H3R together with H2 receptor (H2R) and H4
receptor (H4R) are G-protein-coupled receptor subtypes of histamine
receptors, i.e. receptors binding histamine.
[0154] Without being bound to any theory, the pharmaceutical
composition of the present disclosure can contribute to increase in
inner ear blood flow, such as cochlear and vestibular blood flow,
and/or cerebral blood flow. In another embodiment, the
pharmaceutical composition of the present disclosure can increase
histamine turnover and enhance histamine release in the central
nervous system (CNS), which may rebalance the neuronal activity of
the vestibular nuclei complexes on both sides of the vestibular
system. In one embodiment, the pharmaceutical compositions of the
present disclosure can inhibit neuronal firing in the vestibular
nuclei. In another embodiment, the pharmaceutical composition of
the present disclosure can contribute in up-regulation of
histamine, which induces general brain arousal favoring
sensorimotor activity. In one embodiment, the pharmaceutical
compositions of the present disclosure can facilitate vestibular
compensation and/or central vestibular compensation.
[0155] In one embodiment, the pharmaceutical compositions of the
present disclosure can be useful in treating histamine modulated
diseases or conditions. In another embodiment, the pharmaceutical
composition of the present disclosure can be useful in treating H1R
modulated diseases or conditions. In some embodiments, the
pharmaceutical compositions of the present disclosure can be useful
in treating H3R modulated diseases or conditions.
[0156] In one embodiment, the pharmaceutical compositions of the
present disclosure can be useful in treating obesity, eating
disorders, cognitive disorders, attention deficit disorders, memory
processes, dementia and cognition disorders such as Alzheimer's
disease and attention-deficit hyperactivity disorder, bipolar
disorder, cognitive enhancement, cognitive deficits in psychiatric
disorders, deficits of memory, deficits of learning, dementia, mild
cognitive impairment, migraine, mood and attention alteration,
motion sickness, narcolepsy, neurogenic inflammation, obsessive
compulsive disorder, Parkinson's disease, schizophrenia,
depression, epilepsy, and seizures or convulsions; sleep disorders
such as narcolepsy, vestibular dysfunction such as Meniere's
disease, migraine, motion sickness, pain, drug abuse, depression,
epilepsy, jet lag, wakefulness, Tourette's syndrome, vertigo, and
the like, as well as cardiovascular disorders such as acute
myocardial infarction, cancer such as cutaneous carcinoma,
medullary thyroid carcinoma and melanoma; respiratory disorders
such as asthma, gastrointestinal disorders, inflammation, and
septic shock, diabetes, type II diabetes, insulin resistance
syndrome, metabolic syndrome, polycystic ovary syndrome, Syndrome
X, and the like.
[0157] In one embodiment, the pharmaceutical compositions of the
present disclosure can be useful in treating obesity, attention
deficit hyperactivity disorder, cerebrovascular disease, dementia,
narcolepsy, sleep disorders, Parkinson, addiction, schizophrenia,
Gilles de la Tourette syndrome, and/or Alzheimer's disease.
[0158] In one embodiment, the pharmaceutical compositions of the
present disclosure can be useful in treating or reducing weight
gain. In some embodiments, undesired weight gain may be triggered
by administration of certain drugs. For example, antipsychotic
drugs acting on histamine receptors, such as olanzapine, can
trigger weight gain (Barak et al. Journal of Psychopharmacology,
2016, Vol. 30(3) 237-241; which is incorporated by reference herein
in its entirety). Accordingly, in one embodiment, the present
disclosure provides a method for reducing weight gain induced by
antipsychotic drugs acting on histamine receptors, comprising
intranasally administering the pharmaceutical composition of the
present disclosure.
[0159] In one embodiment of the present disclosure, the betahistine
or a pharmaceutically acceptable salt thereof can be administered
to a subject in need thereof by pathways including nasally (e.g.,
solution, spray, drops, aerosol, gels), orally (e.g., tablets,
capsules, granules, syrups, elixirs, or powders) sublingually,
buccally, parenterally (e.g., subcutaneous, intravenous,
intramuscular, intrathecal, or intracisternal injection), or
infusion techniques (e.g., as sterile injectable aqueous or
non-aqueous solutions or suspensions), topically (e.g.,
drug-releasing skin patch, cream or ointment), intravaginally, by
drench, transdermally, intradermally, pulmonary, by intra-uterine,
by the use of an aerosol, or rectally (e.g., suppositories, in
dosage unit formulations containing nontoxic, pharmaceutically
acceptable vehicles or diluents). In one embodiment, the
betahistine or a pharmaceutically acceptable salt thereof is
administered nasally. In one embodiment, the betahistine or a
pharmaceutically acceptable salt thereof is administered by
intranasal delivery.
[0160] In one embodiment, intranasal delivery of the pharmaceutical
composition of the present disclosure is advantageous for allowing
non-invasive systemic delivery. In another embodiment, the
intranasal delivery of the pharmaceutical composition of the
present disclosure avoids or reduces the first pass metabolism of
betahistine (compared to oral betahistine). In one embodiment, the
intranasal delivery of the pharmaceutical composition of the
present disclosure avoids or reduces the gastric side effects
(compared to oral betahistine). In another embodiment, the
intranasal delivery of the pharmaceutical composition of the
present disclosure is advantageous for achieving rapid onset of
betahistine's action.
[0161] In one embodiment, the pharmaceutical composition of the
present disclosure is administered nasally in drops, spray, gel,
ointment, cream, powder or suspension. In one embodiment, the
pharmaceutical composition of the present disclosure is
administered nasally using a dispenser or a device (for example a
single-dose ampoule, metered spray, an atomizer, a nebulizer, a
pump, a nasal pad, a nasal sponge or a hard gelatin capsule) or any
other method of nasal administration which is known in the
pharmaceutical literature.
[0162] In one embodiment, devices for nasal administration of
liquid pharmaceutical compositions of the present disclosure
include a pipette (e.g. unit dose pipettes); a dropper including
multi-dose droppers; rhinyle catheter; a vapor inhaler; mechanical
spray pumps, including squeeze bottles, multi-dose metered-dose
spray pumps, single or duo-dose spray pumps, bi-directional
multi-dose spray pumps; gas driven spray systems/atomizers and
electrically powered nebulizers/atomizers. In one embodiment,
devices for nasal administration of powder pharmaceutical
compositions of the present disclosure include mechanical powder
sprayers, breath actuated inhalers, and insufflators, including
breath powered bi-directional delivery devices. These devices are
briefly summarized in a review by Djupesland (Drug Deliv. and
Transl. Res. (2013) 3:42-62), which is incorporated by reference
herein in its entirety.
[0163] In one embodiment, the pharmaceutical composition of the
present disclosure is administered to the nasal cavity in metered
doses. In one embodiment, a metered dose nasal spray can be used to
administer the pharmaceutical composition of the present
disclosure. In another embodiment, a metered nasal pump spray can
be used to administer the pharmaceutical composition of the present
disclosure in metered doses. In one embodiment, a metered atomizing
spray pump can be used to administer the pharmaceutical composition
of the present disclosure in metered doses.
[0164] In one embodiment, a nasal pressurized metered-dose inhaler
(pMDI) can be used to administer the pharmaceutical composition of
the present disclosure in metered doses. In one embodiment,
pressurized nasal formulation of the present disclosure can be an
aerosol formulation. Such aerosol formulation, in one embodiment,
includes betahistine or a pharmaceutically acceptable salt thereof
in a pressurized pack with a suitable propellant such as a
hydrofluoroalkanes (HFAs), carbon dioxide, or other suitable
propellant known in the art. The aerosol can, in one embodiment,
also contain a surfactant such as lecithin. The dose of betahistine
or a pharmaceutically acceptable salt thereof can be controlled by
provision of a metered valve.
[0165] In another embodiment, the pharmaceutical composition of the
present disclosure is administered to the nasal cavity by
conventional means, e.g., with a dropper, pipette or spray.
[0166] In one embodiment, a topical pharmaceutical composition of
the present disclosure can be provided in the form of a dry powder,
for example a powder mix of the compound in a suitable powder base
such as lactose, starch, starch derivatives such as
hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). In
one embodiment, the powder carrier will form a gel in the nasal
cavity. The powder composition can be presented in unit dose form
for example in capsules or cartridges of, for example, gelatin, or
blister packs from which the powder can be administered by means of
an inhaler.
[0167] In formulations intended for administration to the
respiratory tract, including intranasal formulations, particle size
of the pharmaceutical composition, when applied, should be less
than 100 micron, less than 50 micron, less than 25 micron, less
than 20 micron, less than 15 micron, or less than 10 micron. In one
embodiment, the particle size of the nasal pharmaceutical
composition is less than 10 micron when applied. In one embodiment,
D.sub.50 of the particle size of the nasal pharmaceutical
composition is less than 10 micron when applied. In one embodiment,
D.sub.90 of the particle size of the nasal pharmaceutical
composition is less than 10 micron when applied.
[0168] In one embodiment, the intranasal pharmaceutical
compositions of the present disclosure in spray form provide a
droplet size distribution Dv(50) of about 150 .mu.m to about 300
.mu.m, including about 160 .mu.m, about 170 .mu.m, about 180 .mu.m,
about 190 .mu.m, about 200 .mu.m, about 210 .mu.m, about 220 .mu.m,
about 230 .mu.m, about 240 .mu.m, about 250 .mu.m, about 260 .mu.m,
about 270 .mu.m, about 280 .mu.m, about 290 .mu.m, or about 300
.mu.m, inclusive of all ranges between any of these values, when
tested at a firing distance of about 20 mm to about 50 mm at firing
force of about 5 kg, about 6 kg, or about 7 kg.
[0169] In one embodiment, the intranasal pharmaceutical
compositions of the present disclosure in spray form provide a
droplet size distribution Dv(90) of about 380 .mu.m to about 650
.mu.m, including about 380 .mu.m, about 390 .mu.m, about 400 .mu.m,
about 410 .mu.m, about 420 .mu.m, about 430 .mu.m, about 440 .mu.m,
about 450 .mu.m, about 460 .mu.m, about 470 .mu.m, about 480 .mu.m,
about 490 .mu.m, about 500 .mu.m, about 510 .mu.m, about 520 .mu.m,
about 530 .mu.m, about 540 .mu.m, about 550 .mu.m, about 560 .mu.m,
about 570 .mu.m, about 580 .mu.m, about 590 .mu.m, about 600 .mu.m,
about 610 .mu.m, about 620 .mu.m, about 630 .mu.m, about 640 .mu.m,
about 650 .mu.m, inclusive of all ranges between any of these
values, when tested at a firing distance of about 20 mm to about 50
mm at firing force of about 5 kg, about 6 kg, or about 7 kg.
[0170] In one embodiment, the pharmaceutical compositions of the
present disclosure are administered 1, 2, 3, 4, 5, 6, 7 8, 9, or 10
times a day. In one embodiment, the pharmaceutical compositions of
the present disclosure are administered one or more times a day,
where each dose administers a controlled, metered, or set amount of
the betahistine or a pharmaceutically acceptable salt thereof.
[0171] In one embodiment, the pharmaceutical compositions of the
present disclosure are administered to the nasal cavity in a unit
dose containing about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 26, 27, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,
47, 48, 49, or 50 mg of betahistine or a pharmaceutically
acceptable salt thereof. For example, if a metered nasal spray is
used, one spray dose contains about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 49, or 50 mg of betahistine or a pharmaceutically
acceptable salt thereof. In another embodiment, the present
disclosure is administered to the nasal cavity in a unit dose
containing about 10, 15, 20, 25, 30, 35, 40, 45, or 50 mg of
betahistine or a pharmaceutically acceptable salt thereof. In one
embodiment, the present disclosure is administered to the nasal
cavity in a unit dose containing about 20 mg of betahistine or a
pharmaceutically acceptable salt thereof.
[0172] In one embodiment, the pharmaceutical compositions of the
present disclosure are administered to the nasal cavity in a unit
dose containing about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,
105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165,
170, 175, 180, 185, 190, 195, or 200 mg of betahistine or a
pharmaceutically acceptable salt thereof.
[0173] In one embodiment, the pharmaceutical compositions of the
present disclosure are administered to the nasal cavity in a unit
dose or a metered dose which provides dose content uniformity with
relative standard deviation of less than 5.0%, less than 4.5%, less
than 4.0%, less than 3.5%, less than 2.0%, less than 1.5%, less
than 1.0%, or less than 0.5%.
[0174] In one embodiment, the intranasal pharmaceutical
compositions of the present disclosure are administered 1, 2, 3, 4,
5, 6, 7 8, 9, or 10 times a day. In one embodiment, the intranasal
pharmaceutical compositions of the present disclosure are
administered once a day, twice a day, three times a day, four times
a day, five times a day, or six times a day where each dose
administers a controlled, metered, or set amount of the betahistine
or a pharmaceutically acceptable salt thereof. In some embodiments,
the intranasal pharmaceutical composition of the present disclosure
is administered three times a day. In some embodiments, the
intranasal pharmaceutical compositions of the present disclosure
are administered up to six times a day.
[0175] In one embodiment, the intranasal pharmaceutical composition
of the present disclosure is administered to provide daily dose of
betahistine or a pharmaceutically acceptable salt thereof in about
0.01 mg/kg to about 20 mg/kg bodyweight of a human patient,
including about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg,
about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07
mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about
0.12 mg/kg, about 0.14 mg/kg, about 0.16 mg/kg, about 0.18 mg/kg,
about 0.2 mg/kg, about 0.22 mg/kg, about 0.24 mg/kg, about 0.26
mg/kg, about 0.28 mg/kg, about 0.3 mg/kg, about 0.32 mg/kg, about
0.34 mg/kg, about 0.36 mg/kg, about 0.38 mg/kg, about 0.4 mg/kg,
about 0.42 mg/kg, about 0.44 mg/kg, about 0.46 mg/kg, about 0.48
mg/kg, about 0.5 mg/kg, about 0.52 mg/kg, about 0.54 mg/kg, about
0.56 mg/kg, about 0.58 mg/kg, about 0.6 mg/kg, about 0.62 mg/kg,
about 0.64 mg/kg, about 0.66 mg/kg, about 0.68 mg/kg, about 0.7
mg/kg, about 0.72 mg/kg, about 0.74 mg/kg, about 0.76 mg/kg, about
0.78 mg/kg, about 0.8 mg/kg, about 0.82 mg/kg, about 0.84 mg/kg,
about 0.86 mg/kg, about 0.88 mg/kg, about 0.9 mg/kg, about 0.92
mg/kg, about 0.94 mg/kg, about 0.96 mg/kg, about 0.98 mg/kg, about
1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about
1.4, mg/kg about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about
1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about
2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about
2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about
3 mg/kg, about 3.1 mg/kg, about 3.2 mg/kg, about 3.3 mg/kg, about
3.4 mg/kg, about 3.5 mg/kg, about 3.6 mg/kg, about 3.7 mg/kg, about
3.8 mg/kg, about 3.9 mg/kg, about 4 mg/kg, about 4.1 mg/kg, about
4.2 mg/kg, about 4.3 mg/kg, about 4.4 mg/kg, about 4.5 mg/kg, about
4.6 mg/kg, about 4.7 mg/kg, about 4.8 mg/kg, about 4.9 mg/kg, about
5 mg/kg, about 5.1 mg/kg, about 5.2 mg/kg, about 5.3 mg/kg, about
5.4 mg/kg, about 5.5 mg/kg, about 5.6 mg/kg, about 5.7 mg/kg, about
5.8 mg/kg, about 5.9 mg/kg, about 6 mg/kg, about 6.1 mg/kg, about
6.2 mg/kg, about 6.3 mg/kg, about 6.4 mg/kg, about 6.5 mg/kg, about
6.6 mg/kg, about 6.7 mg/kg, about 6.8 mg/kg, about 6.9 mg/kg, about
7 mg/kg, about 7.1 mg/kg, about 7.2 mg/kg, about 7.3 mg/kg, about
7.4 mg/kg, about 7.5 mg/kg, about 7.6 mg/kg, about 7.7 mg/kg, about
7.8 mg/kg, about 7.9 mg/kg, about 8 mg/kg, about 8.1 mg/kg, about
8.2 mg/kg, about 8.3 mg/kg, about 8.4 mg/kg, about 8.5 mg/kg, about
8.6 mg/kg, about 8.7 mg/kg, about 8.8 mg/kg, about 8.9 mg/kg, about
9 mg/kg, about 9.1 mg/kg, about 9.2 mg/kg, about 9.3 mg/kg, about
9.4 mg/kg, about 9.5 mg/kg, about 9.6 mg/kg, about 9.7 mg/kg, about
9.8 mg/kg, about 9.9 mg/kg, about 10 mg/kg, about 11.1 mg/kg, about
11.2 mg/kg, about 11.3 mg/kg, about 11.4, mg/kg about 11.5 mg/kg,
about 11.6 mg/kg, about 11.7 mg/kg, about 11.8 mg/kg, about 11.9
mg/kg, about 12 mg/kg, about 12.1 mg/kg, about 12.2 mg/kg, about
12.3 mg/kg, about 12.4 mg/kg, about 12.5 mg/kg, about 12.6 mg/kg,
about 12.7 mg/kg, about 12.8 mg/kg, about 12.9 mg/kg, about 13
mg/kg, about 13.1 mg/kg, about 13.2 mg/kg, about 13.3 mg/kg, about
13.4 mg/kg, about 13.5 mg/kg, about 13.6 mg/kg, about 13.7 mg/kg,
about 13.8 mg/kg, about 13.9 mg/kg, about 14 mg/kg, about 14.1
mg/kg, about 14.2 mg/kg, about 14.3 mg/kg, about 14.4 mg/kg, about
14.5 mg/kg, about 14.6 mg/kg, about 14.7 mg/kg, about 14.8 mg/kg,
about 14.9 mg/kg, about 15 mg/kg, about 15.1 mg/kg, about 15.2
mg/kg, about 15.3 mg/kg, about 15.4 mg/kg, about 15.5 mg/kg, about
15.6 mg/kg, about 15.7 mg/kg, about 15.8 mg/kg, about 15.9 mg/kg,
about 16 mg/kg, about 16.1 mg/kg, about 16.2 mg/kg, about 16.3
mg/kg, about 16.4 mg/kg, about 16.5 mg/kg, about 16.6 mg/kg, about
16.7 mg/kg, about 16.8 mg/kg, about 16.9 mg/kg, about 17 mg/kg,
about 17.1 mg/kg, about 17.2 mg/kg, about 17.3 mg/kg, about 17.4
mg/kg, about 17.5 mg/kg, about 17.6 mg/kg, about 17.7 mg/kg, about
17.8 mg/kg, about 17.9 mg/kg, about 18 mg/kg, about 18.1 mg/kg,
about 18.2 mg/kg, about 18.3 mg/kg, about 18.4 mg/kg, about 18.5
mg/kg, about 18.6 mg/kg, about 18.7 mg/kg, about 18.8 mg/kg, about
18.9 mg/kg, about 19 mg/kg, about 19.1 mg/kg, about 19.2 mg/kg,
about 19.3 mg/kg, about 19.4 mg/kg, about 19.5 mg/kg, about 19.6
mg/kg, about 19.7 mg/kg, about 19.8 mg/kg, about 19.9 mg/kg, or
about 20 mg/kg, inclusive of all ranges between any of these
values.
[0176] In one embodiment, the intranasal pharmaceutical
compositions of the present disclosure are administered to provide
a daily dose of betahistine or a pharmaceutically acceptable salt
thereof in about 1 mg to about 200 mg per patient. In another
embodiment, an intranasal pharmaceutical composition of the present
disclosure is administered to provide a daily dose of betahistine
or a pharmaceutically acceptable salt thereof in about 5 mg to
about 100 mg.
[0177] In one embodiment, the intranasal pharmaceutical
compositions of the present disclosure comprise betahistine or a
pharmaceutically acceptable salt thereof in a concentration of
about 1 mg/mL to about 1000 mg/mL. In another embodiment, the
intranasal pharmaceutical composition of the present disclosure
comprises betahistine or a pharmaceutically acceptable salt thereof
in about 10 mg/mL to about 400 mg/mL, including about 10 mg/mL,
about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL,
about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, about 50 mg/mL,
about 55 mg/mL, about 60 mg/mL, about 65 mg/mL, about 70 mg/mL,
about 75 mg/mL, about 80 mg/mL, about 85 mg/mL, about 90 mg/mL,
about 95 mg/mL, about 100 mg/mL, about 105 mg/mL, about 110 mg/mL,
about 115 mg/mL, about 120 mg/mL, about 125 mg/mL, about 130 mg/mL,
about 135 mg/mL, about 140 mg/mL, about 145 mg/mL, about 150 mg/mL,
about 155 mg/mL, about 160 mg/mL, about 165 mg/mL, about 170 mg/mL,
about 175 mg/mL, about 180 mg/mL, about 185 mg/mL, about 190 mg/mL,
about 195 mg/mL, about 200 mg/mL, about 205 mg/mL, about 210 mg/mL,
about 215 mg/mL, about 220 mg/mL, about 225 mg/mL, about 230 mg/mL,
about 235 mg/mL, about 240 mg/mL, about 245 mg/mL, about 250 mg/mL,
about 255 mg/mL, about 260 mg/mL, about 265 mg/mL, about 270 mg/mL,
about 275 mg/mL, about 280 mg/mL, about 285 mg/mL, about 290 mg/mL,
about 295 mg/mL, about 300 mg/mL, about 305 mg/mL, about 310 mg/mL,
about 315 mg/mL, about 320 mg/mL, about 325 mg/mL, about 330 mg/mL,
about 335 mg/mL, about 340 mg/mL, about 345 mg/mL, about 350 mg/mL,
about 355 mg/mL, about 360 mg/mL, about 365 mg/mL, about 370 mg/mL,
about 375 mg/mL, about 380 mg/mL, about 385 mg/mL, about 390 mg/mL,
about 395 mg/mL, or about 400 mg/mL, including all ranges between
any of these values.
[0178] In one embodiment, the intranasal pharmaceutical
compositions of the present disclosure comprise betahistine or a
pharmaceutically acceptable salt thereof in administered in a unit
dose or metered dose of about 1 .mu.L to about 1000 including about
1 about 10 .mu.L, about 20 about 30 about 40 about 50 about 60
about 70 about 80 .mu.L, about 90 about 100 about 110 about 120
.mu.L, about 130 .mu.L, about 140 .mu.L, about 150 .mu.L, about 160
.mu.L, about 170 .mu.L, about 180 .mu.L, about 190 about 200 about
210 about 220 .mu.L, about 230 about 240 about 250 about 260 about
270 about 280 .mu.L, about 290 about 300 about 310 about 320 .mu.L,
about 330 .mu.L, about 340 .mu.L, about 350 .mu.L, about 360 .mu.L,
about 370 .mu.L, about 380 .mu.L, about 390 about 400 about 410
about 420 .mu.L, about 430 about 440 about 450 about 460 about 470
about 480 .mu.L, about 490 about 500 about 510 about 520 .mu.L,
about 530 .mu.L, about 545 .mu.L, about 550 .mu.L, about 560 .mu.L,
about 570 .mu.L, about 580 .mu.L, about 590 about 600 about 610
about 620 .mu.L, about 630 about 640 about 650 about 660 about 670
about 680 .mu.L, about 690 about 700 about 710 about 720 .mu.L,
about 730 .mu.L, about 740 .mu.L, about 750 .mu.L, about 760 .mu.L,
about 770 .mu.L, about 780 .mu.L, about 790 about 800 about 810
about 820 .mu.L, about 830 about 840 about 850 about 860 about 870
about 880 .mu.L, about 890 about 900 about 910 about 920 .mu.L,
about 930 .mu.L, about 940 .mu.L, about 950 .mu.L, about 960 .mu.L,
about 970 .mu.L, about 980 .mu.L, about 990 .mu.L, or about 1000
.mu.L, including all ranges between any of these values. In some
embodiments, the intranasal pharmaceutical compositions of the
present disclosure comprise betahistine or a pharmaceutically
acceptable salt thereof in administered in a unit dose or metered
dose of about 10 .mu.L to about 200 .mu.L. In another embodiment,
the intranasal pharmaceutical composition of the present disclosure
comprises betahistine or a pharmaceutically acceptable salt thereof
in administered in a unit dose or metered dose of about 10 .mu.L to
about 100 .mu.L.
[0179] In one embodiment, a unit dose or a metered dose of an
intranasal pharmaceutical composition of the present disclosure
comprising betahistine or a pharmaceutically acceptable can be
administered in one unit or metered dose at a time, two unit or
metered doses at a time, three unit or metered doses at a time, or
four unit or metered doses at a time.
[0180] In one embodiment, a treatment cycle with the pharmaceutical
composition of the present disclosure can be about 1 day to about 7
days, about 1 week to about 5 weeks, or about 1 month to about 12
months. In one embodiment, a treatment cycle with the intranasal
pharmaceutical composition can be about 1 day to about 7 days,
about 1 week to about 5 weeks, or about 1 month to about 12 months.
In one embodiment, a treatment cycle with the intranasal
pharmaceutical composition can be about 1 month, about 2 months,
about 3 months, about 4 months, about 5 months, about 6 months,
about 7 months, about 8 months, about 9 months, about 10 months,
about 11 months, or about 12 months. In one embodiment, a treatment
cycle with the intranasal pharmaceutical composition can be about 3
month or about 6 months. In one embodiment, a treatment cycle with
an intranasal pharmaceutical composition of the present disclosure
can be more than one year. In another embodiment, the treatment
cycle can be more than one year, more than 1.5 years, more than 2
years, more than 2.5 years, more than 3 years, more than 4 years,
or more than 5 years. The appropriate length of a treatment with
the pharmaceutical composition of the present disclosure can be
determined by a patient's physician and used as directed.
[0181] In one embodiment, a pharmaceutical composition of the
present disclosure is a solution, suspension, powder, or aerosol.
In one embodiment, the pharmaceutical composition of the present
disclosure is an aqueous solution.
[0182] In one embodiment, the pharmaceutical compositions of the
present disclosure can be administered in combination with at least
one of enzyme inhibitors or absorption promoters. In one
embodiment, at least one enzyme inhibitor is selected from
betastatin, amastatin, boroleucin, borvovaline, aprotinin, trypsin
inhibitors, fusidic acids, and bile salts. In another embodiment,
at least one absorption promoter is selected from
.beta.-cyclodextrin, fusidic acid derivatives (sodium
taurodihydrofusidate), microspheres, liposomes, bile salts,
lauareth-9, saponins, BL-9, glycolate, chitosan,
dideanoyl-L-phosphatidylcholine, and lysophosphatidylcholine.
[0183] In one embodiment, the pharmaceutical compositions of the
present disclosure can further comprise at least one additional
pharmaceutically active agent. In some embodiments, at least one
additional pharmaceutically active agent is a drug that treats
vestibular disorders, neurotological disorders, otological and/or
neurological disorders. In some embodiments, at least one
additional pharmaceutically active agent is a drug that treats
inner ear dysfunctions or inner ear disorders and/or a drug that
treats or alleviates symptoms of inner ear disorders and
dysfunctions.
[0184] In one embodiment, the at least one additional
pharmaceutically active agent is selected from a group of glutamate
receptor modulators. Non limiting examples of glutamate receptor
modulators include glutamate receptor antagonists, AMPA
(.alpha.-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)
receptor antagonists, and NMDA (N-methyl-D-aspartate) receptor
antagonists. In one embodiment, an AMPA receptor antagonist is
selected from 6-cyano-7-nitroquinoxaline-2,3-dione,
2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione),
6,7-dinitroquinoxaline-2,3-dione, kynurenic acid,
2,3-dihydroxy-6-nitro-7-sulfamoylbenzo-[f]quinoxaline, or a
combination thereof.
[0185] In one embodiment, a glutamate receptor antagonist,
including NMDA receptor antagonist, is selected from
1-aminoadamantane; dextromethorphan; dextrorphan; ibogaine;
ifenprodil; (S)-ketamine; (R)-ketamine; memantine; dizocilpine;
gacyclidine; traxoprodil; D-2-amino-5-phosphonopentanoic acid;
3-((.+-.)2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid;
conantokin; 7-chlorokynurenate; licostinel; nitrous oxide;
phencyclidine; riluzole; tiletamine; aptiganel; remacimide;
5,7-dichlorokynurenic acid; kynurenic acid;
1-aminocyclopropanecarboxylic acid; 2-amino-7-phosphonoheptanoic
acid; R-2-amino-5-phosphonopentanoate;
3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid;
(+)-(1S,2S)-1-(4-hydroxy-phenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propa-
nol;
(1S,2S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-4-phenylpiperi-din-
o)-1-propanol;
(3R,4S)-3-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl-)-chroman-4,7-diol;
(1R*,2R*)-1-(4-hydroxy-3-methylphenyl)-2-(4-(4-fluoro-phenyl)-4-hydroxypi-
peridin-1-yl)-propan-1-ol-mesylate; or combinations thereof.
EXAMPLES
Example 1: Sample Formulation
[0186] Intranasal delivery formulations of the pharmaceutical
compositions in accordance with the present disclosure comprising
betahistine dihydrochloride were supplied by Otifex Therapeutics
and stored in a desiccator at ambient conditions until
required.
[0187] Formulations with 10, 50 or 200 mg/mL betahistine were
prepared as follows:
[0188] 10 mg/mL Betahistine formulation. 20 mg of benzalkonium
chloride (heated to approximately 65.degree. C. to aid transfer)
and 20 mg of edetate disodium were added into the same beaker and
dissolved in approximately 10 mL of water for injection using a
stirrer. 1 g of betahistine dihydrochloride was put into a sterile
plastic bottle and 97.5 mg of sodium phosphate dibasic and 552.5 mg
of sodium phosphate monobasic were added thereto. Approximately 25
mL of water for injection was added to the bottle and the resulting
solution was mixed thoroughly. Then, 100 mg of glycerin, 1.25 g of
polyvinyl pyrrolidone, 3.75 g of polyethylene glycol 400 and 2 g of
propylene glycol were added (using small amounts of water for
transfer). To the resulting mixture, the prepared benzalkonium
chloride and edetate disodium solution was added, using
approximately 10 mL of water for injection.
[0189] The pH of the resulting solution was adjusted to pH 5.0 by
adding 3.88 mL of 1M sodium hydroxide. The pH of the solution was
checked before quantitatively transferring it into a 100 mL
volumetric flank using small amount of water for injection.
[0190] Water for injection was added to obtain 100 mL of
formulation. The pH was re-checked/adjusted to 5.0 and the
formulation was stored at 2-8.degree. C. until required.
[0191] The 10 mg/mL betahistine intranasal formulation thus
prepared contained the following constituents (all concentrations
provided as weight/weight, unless otherwise indicated): 1.0%
betahistine dihydrochloride as active substance, 0.1% glycerin,
3.75% polyethylene glycol 400 and 2% propylene glycol as
moisturizing agents, 1.25% polyvinyl pyrrolidone for viscosity and
to increase nasal ciliary clearance, 0.02% edetate disodium as
preservative/stabilizer, 0.02% benzalkonium chloride as
preservative, 0.0975% sodium phosphate dibasic and 0.5525% sodium
phosphate monobasic as buffer, 1 M sodium hydroxide 3.88 mL for pH
adjustment to 5.0, and water for injection q.s. to 100 mL as
solvent.
[0192] 50 and 200 mg/mL Betahistine formulation. The concentration
of betahistine dihydrochloride required was 5.0 and 20.0%,
respectively, and the amount of 5 M sodium hydroxide 4.38 mL and of
10 M sodium hydroxide 9.3 mL, respectively.
TABLE-US-00002 TABLE 2 Sample Formulation Prepared by Example 1
Concentration Constituent Amount (mg/mL) Function Betahistine 1 g
10.0 Active Substance Dihydrochloride 5 g 50.0 20 g 200.0
Benzalkonium 20 mg 0.2 Preservative Chloride Glycerin 100 mg 1.0
Moisturizing Agent Edetate Disodium 20 mg 0.2
Preservative/Stabilizer Polyvinyl 1.25 g 12.5 Viscosity/Nasal
Pyrrolidone Ciliary Clearance Polyethylene 3.75 g 37.5 Moisturizing
Agent Glycol 400 Propylene Glycol 2 g 20 Moisturizing Agent Sodium
Phosphate 97.5 mg 0.975 Buffer Dibasic Sodium Phosphate 552.5 mg
5.525 Buffer Monobasic 1M Sodium 3.88 mL pH adjustment Hydroxide
4.38 mL to 5.0 9.3 mL Water to 100 mL Solvent
Example 2: Safety and Pharmacokinetic Profile Evaluation in
Dogs
[0193] The safety and pharmacokinetic profile of intranasal
betahistine was first evaluated in a single dose toxicology study
in male and female beagle dogs (14-21 months of age, weight
8.2-11.8 kg). Both the vehicle and test article were delivered in a
single dose via a nasal spray pump (Aptar Classic Line) with a
delivery volume of 100 .mu.L into both nostrils at total dose
levels of 0 (vehicle), 4, 20 or 80 mg of betahistine
dihydrochloride. Each treatment group was made up of 1 dog/sex.
Animals were observed for 7 days, then allowed a 3-day washout
period prior to being used for a repeat-dose study, where they
received for 14 consecutive days daily in three doses separated by
approximately 4 hours 0 (vehicle), 12, 60 or 240 mg of betahistine
dihydrochloride.
[0194] For toxicokinetic assessments blood samples were collected
as follows: prior to dosing and approximately 5, 15 and 30 minutes,
1, 2, 6, 24 and 168 hours following dosing in the single-dose phase
and prior to the first dose on study days 1, 8 and 14 as well as 2
hours following the third dose of the day on study days 1 and 14 as
well as on study day 15, prior to necropsy. Plasma concentrations
were measured with liquid chromatographic tandem mass spectrometry
(LC-MS/MS; SCIEX API 5000 for betahistine and SCIEX API 4000 for
2-pyridylacetic acid (2-PAA)) with a validated method.
Betahistine-.sup.13CD.sub.3 dihydrochloride and 2-PAA-D.sub.4
hydrochloride served as internal standards. The standard
calibration range--using a plasma sample volume of 0.05 mL--for
betahistine was 0.05 to 50 ng/mL and for 2-PAA it was 1 to 1000
ng/mL. The limit of quantitation was 0.05 ng/mL for betahistine and
1.0 ng/mL for 2-PAA.
[0195] In case of betahistine, the method involved a liquid-liquid
extraction; in case of 2-PAA it involved protein precipitation. For
betahistine, plasma samples were extracted under basic conditions
with an organic solvent; the organic phase was dried and
reconstituted in reconstitution solvent. Approximately 0.1 mL of
the aqueous layer was transferred into polypropylene vials for
LC-MS/MS analysis. For 2-PAA, plasma samples were precipitated with
a mixture of organic solvents, supernatant was diluted and 0.12 mL
was transferred into polypropylene vials for LC-MS/MS analysis.
Sample analysis was conducted using reversed phase
chromatography.
[0196] Intranasal betahistine was well tolerated. Test
article-related clinical signs consisting of mild to moderate
salivation were noted following intranasal delivery of 80 mg of the
test article in both the single dose and the repeated-dose (240
mg/day) phase of the study. Salivation after betahistine treatment
was previously reported to occur in dogs, it was transient in
nature in the present study and resolved quickly. Body weights,
clinical pathology and gross necropsy findings were unremarkable.
No adverse treatment-related microscopic findings were noted in the
study.
[0197] Betahistine was rapidly absorbed following single dose
intranasal administration, with the peak concentration observed at
the 5-minute time point (T.sub.max) (FIG. 1). Without being bound
to any theory, the T.sub.max of 5 minutes post-dose suggests rapid
onset of betahistine's pharmacological activity. The increase in
C.sub.max was linear to the dose administered, but not
proportional--C.sub.max amounted to 26, 81 and 248 ng/mL for the 4,
20 and 80 mg groups (average for male and female animals).
Concentrations declined rapidly by more than 90% at the 1-hour
time-point. Quantifiable plasma concentrations were no longer
observable after the 2- or 6-hour time-points in the 4 and 20 mg
dose groups, but were observed out to the 24-hour time-point in the
80 mg dose group. The 2-PAA metabolite, like its parent, appeared
rapidly by the 5-minute time-point, indicating rapid formation at
similar rates across the dose levels evaluated (FIG. 2). 2-PAA
reached peak concentrations of 606, 2195 and 4615 ng/mL for the 4,
20 and 80 mg groups (average for male and female animals) at times
ranging between 15 minutes and 1 hour. The increases in C.sub.max
were roughly dose-proportional between 4 and 20 mg dose groups and
less than proportional between the 20 and 80 mg dose groups,
indicating a saturation of the elimination process above the 20 mg
dose level. Following the peak levels, 2-PAA declined rapidly and
approximately linearly, in general with the last measurable values
at 24 hours post-dose.
[0198] In the repeated-dose evaluation, there were measurable
levels of betahistine and 2-PAA in all collected samples in the 20
and 80 mg dose groups, and in most samples of the 4 mg dose group.
The increases in betahistine concentration across dose levels were
less than proportional at comparable plasma sampling times.
Although overall betahistine was rapidly eliminated, small plasma
concentration levels could still be observed in trough samples from
study days 8 and 14, suggesting maintenance of some, albeit low
basal level.
[0199] The results from the single-dose and repeated-dose
toxicology study show that intranasal betahistine is feasible and
results in rapid and meaningful systemic exposure. The treatment
was well tolerated in dogs.
Example 3: Safety and Pharmacokinetic Profile Evaluation in
Humans
[0200] The safety and pharmacokinetic profile of intranasal
betahistine was further evaluated in a double-blind, randomized,
placebo-controlled, single ascending-dose clinical trial involving
a total of 32 healthy male and female volunteers. The main
inclusion criteria were that subjects had to be aged 18-45 years
and show a body mass index within the range of 18-30 kg/m.sup.2.
Subjects were required to fast for 8 hours prior to study drug
administration and for 2 hours post-dose. Water was withheld from 1
hour prior to study drug administration and for 1 hour
post-dose.
[0201] Betahistine dihydrochloride was tested in four dose cohorts
at 5, 10, 20 and 40 mg; in each cohort 6 subjects received the
active drug and 2 subjects received matching placebo. The
betahistine was supplied as a 50 and 200 mg/mL solution in a HDPE
bottle and spray pump pack (Aptar Classic Line) that delivers an
accurate 100 .mu.L per actuation. The study drug was delivered into
the right nostril of subjects while they were in a supine position.
For the 5 and 20 mg doses, one application of 50 and 200 mg/mL,
respectively, was needed, whereas for the 10 and 40 mg doses, two
applications of 50 and 200 mg/mL were required.
[0202] Serial blood samples were collected through 24 hours,
following dosing on Day 1, at Day 4 and Day 7 to determine
concentrations of betahistine and its main metabolite, 2-PAA in
plasma. Plasma samples were assayed for BH content using validated
procedures and methods. Blood samples (6 mL) were collected into
tubes containing K.sub.2EDTA and were centrifuged at approximately
2000 g for 10 minutes at +4.degree. C. and the resultant plasma
transferred into 2 clean, labelled 2 mL cryovials. All plasma
samples were stored at -70.degree. C. or below until all samples
had been collected and sent as a single batch for analysis. Aliquot
1 and 2 were sent as separate shipments. Concentrations were
determined using liquid chromatographic tandem mass spectrometry
(LC-MS/MS; SCIEX API 5000 for betahistine and SCIEX API 4000 for
2-PAA) with a validated method. Betahistine-.sup.13CD.sub.3
dihydrochloride and 2-PAA-D.sub.4 hydrochloride served as internal
standards. The standard calibration range--using a plasma sample
volume of 0.2 and 0.1 mL, respectively--for betahistine was 10 to
800 pg/mL and for 2-PAA it was 2 to 2000 ng/mL. The limit of
quantitation was 10 pg/mL for betahistine and 2.0 ng/mL for
2-PAA.
[0203] In case of betahistine, the method involved a liquid-liquid
extraction; in case of 2-PAA it involved protein precipitation. For
betahistine, plasma samples were extracted under basic conditions
with an organic solvent; the organic phase was dried and
reconstituted in reconstitution solvent. Approximately 0.120 mL of
the aqueous layer was transferred into polypropylene vials for
LC-MS/MS analysis. For 2-PAA plasma samples were precipitated with
a mixture of organic solvents, supernatant was diluted and 0.120 mL
was transferred into polypropylene vials for LC-MS/MS analysis.
Sample analysis was conducted using reversed phase
chromatography.
[0204] The treatment with betahistine at the tested doses of 5, 10,
20 and 40 mg was well tolerated. There were no differences in
hematology, biochemistry, urinalysis, vital signs and
electrocardiogram assessments between active- and placebo-treated
subjects. The incidence of treatment-emergent adverse events was
also similar for both groups of subjects, and there was no apparent
dose-related trend in the incidence of adverse events for
active-treated subjects. Pharmacokinetic parameters of systemic
exposure of betahistine and 2-PAA increased with dose level. For
betahistine, peak concentrations in plasma were 4.1 and 10.5 ng/mL
for the two highest doses (FIG. 3), which is markedly higher than
the C.sub.max of <0.5 ng/mL reported by Chen et al.
(Xenobiotica, 2003, 3(12)3, 1261) following oral administration of
betahistine 24 mg. The peak was achieved at approximately 10
minutes post-dose. For the metabolite 2-PAA peak concentrations
were 370 and 519 ng/mL for the two highest doses (FIG. 4), which is
similar to the level re-ported by Val et al.
(Arzneimittelforschung, 2010, 60(7), 440) following oral
administration of betahistine 16 mg (522 ng/mL). T.sub.max was
reached after 1.2 hours, which is also similar to results from
studies with oral administration of betahistine 16 or 50 mg,
reported by Chen et al. (2003) at 1 hour and Moorthy et al.
(Biopharm. Drug Dispos., 2015, 36(12), 429) at 1.5 hours.
[0205] For each subject who completed the study, plasma
concentration-time data of betahistine and 2-PAA were used for the
calculation of the following pharmacokinetic parameters: [0206]
C.sub.max Maximum observed plasma concentration obtained directly
from the data. [0207] t.sub.max Time to maximum observed
concentration, taken directly from the data. If the maximum plasma
concentration occurred at more than one time point, the first was
chosen. [0208] AUC.sub.0-last Area under the plasma concentration
versus time curve, calculated using the linear trapezoidal rule
from time 0 to time t, where t is the time of last quantifiable
concentration. [0209] .lamda..sub.z Terminal elimination rate
constant obtained from the slope of the line, fitted by linear
least squares regression through the terminal points of the
logarithmic concentration-time profiles (sometimes also referred to
as k.sub.el). [0210] AUC.sub.0-inf Area under the plasma
concentration versus time curve from zero to infinity, calculated
as (AUC.sub.0-t+C.sub.t/.lamda..sub.z), where C.sub.t is the last
quantifiable concentration. [0211] t.sub.1/2 Apparent terminal
half-life, calculated as t.sub.1/2=ln(2)/.lamda..sub.z.
[0212] Dose normalized parameters C.sub.max/Dose and AUC/Dose were
also calculated.
[0213] A summary of the determined pharmacokinetic parameters of
betahistine by treatment is given in Tables 3-4.
TABLE-US-00003 TABLE 3 Summary of Pharmacokinetic Parameters of
Betahistine Mean (CV %) Median C.sub.max AUC.sub.0-last
AUC.sub.0-inf (range) Dose (pg/ (hr*pg/ (hr*pg/ t.sub.1/2 t.sub.max
Cohort * (mg) N mL) mL) mL) (hr) (hr) Cohort 1 5 mg 6 638 209 277
.sup.a 0.208 .sup.a 0.208 Linear (67%) (75%) (60%) (83%)
(0.08-0.33) Cohort 2 10 mg 6 2112 533 697 .sup.a 0.883 .sup.a 0.167
Linear (46%) (45%) (39%) (140%) (0.08-0.17) Cohort 3 20 mg 6 4105
1608 1626.sup. 0.519.sup. 0.167 Linear (53%) (65%) (65%) (116%)
(0.08-0.33) Cohort 4 40 mg 6 10490 3531 2941 .sup.b 0.926 .sup.b
0.125 Linear (26%) (31%) (2.3%) (108%) (0.08-0.27) Key: .sup.a n =
3; .sup.b n = 2; NA = Not applicable (n = 0) * Linear conducted at
Linear Clinical Research.
TABLE-US-00004 TABLE 4 Additional Pharmacokinetic Parameters of
Betahistine Pharmacokinetic Dose CV Parameter Cohort (mg) N Mean
(%) Kel (1/hr) 1 L 5 3 5.09 68% Kel (1/hr) 2 L 10 3 2.83 78% Kel
(1/hr) 3 L 20 6 2.27 48% Kel (1/hr) 4 L 40 2 1.79 108%
[0214] A summary of the determined pharmacokinetic parameters of
2-PAA is given in Tables 5-6.
TABLE-US-00005 TABLE 5 Summary of Pharmacokinetic Parameters of
2-PAA Mean (CV %) Median C.sub.max AUC.sub.0-last AUC.sub.0-inf
(range) Dose (ng/ (hr*ng/ (hr*ng/ t.sub.1/2 t.sub.max Cohort * (mg)
N mL) mL) mL) (hr) (hr) Cohort 1 5 mg 6 67.8 387 427 4.36 1.008
Linear (61%) (57%) (54%) (41%) (1.00-1.50) Cohort 2 10 mg 6 148 736
768 3.76 1.250 Linear (19%) (13%) (13%) (29%) (0.55-2.00) Cohort 3
20 mg 6 370 2000 2029 3.49 1.250 Linear (19%) (13%) (13%) (29%)
(0.50-1.50) Cohort 4 40 mg 6 519 2828 2901 3.93 1.000 Linear (29%)
(24%) (24%) (23%) (1.00-1.50) Key: .sup.a n = 3; .sup.b n = 2; NA =
Not applicable (n = 0) * Linear conducted at Linear Clinical
Research.
TABLE-US-00006 TABLE 6 Additional Pharmacokinetics parameters of
2-PAA Pharmacokinetic Dose CV Parameter Cohort (mg) N Mean (%) Kel
(1/hr) 1 L 5 6 0.180 36% Kel (1/hr) 2 L 10 6 0.199 30% Kel (1/hr) 3
L 20 6 0.203 18% Kel (1/hr) 4 L 40 6 0.187 32%
[0215] The above data in Tables 3-6 indicate that pharmacokinetic
parameters of systemic exposure of betahistine and 2-PAA increased
with dose level. Graphical presentation of the dose response
suggests that the exposure of betahistine is dose proportional
across the betahistine dose range in this study of 5 to 40 mg. For
betahistine, peak concentrations are achieved at 5 to 20 minutes,
and the apparent half-life is less than 1 hour. For the metabolite
2-PAA, peak concentrations are achieved at approximately 1-1.25
hours post-dose (range 20 minutes to 2 hours), and the apparent
half-life is approximately 4 hours.
[0216] In summary, the results from this study show that intranasal
betahistine is well tolerated and--unlike oral
administration--provides for quantifiable and meaningful plasma
concentrations of the active parent compound. The peak
concentration is reached about 10 minutes post-dose and without
being bound to any theory, suggests a rapid onset of action, which
can be of particular therapeutic utility e.g. in case of acute
medical need. The experiment shows for the first time that
betahistine can be effectively and safely administered systemically
in a non-invasive way by the intranasal route.
Example 4: Dose Content Uniformity
[0217] Formulations with 10 and 200 mg/mL betahistine were prepared
according to Example 1 and Table 2 with the exception of adjustment
of pH value to 5.5.
[0218] Formulations were filled into 100 .mu.L Aptar Classic Line
pump sprays and then fired into an appropriate volumetric flask,
made to volume with diluent. Tables 7-8 show dose content
uniformity.
TABLE-US-00007 TABLE 7 Dose Content Uniformity of 10 mg/mL
Formulation Prep Assay .mu.g % Mean 1 1.02443 103.2 2 1.00160 100.9
3 0.97018 97.8 4 0.99444 100.2 5 0.96749 97.5 6 1.02161 102.9 7
0.99941 100.7 8 0.94260 95.0 9 1.01197 102.0 10 0.99125 99.9
Average 0.99 % RSD 2.60
TABLE-US-00008 TABLE 8 Dose Content Uniformity of 200 mg/mL
Formulation Prep Assay .mu.g % Mean 1 20.51925 99.3 2 20.45679 99.0
3 20.66933 100.0 4 20.87421 101.0 5 20.83816 100.8 6 20.32822 98.4
7 20.54321 99.4 8 20.43937 98.9 9 20.91649 101.2 10 21.05841 101.9
Average 20.66 % RSD 1.18
Example 5: Pharmacokinetic Profile Evaluation in Dogs
[0219] In this study, the pharmacokinetic profile of betahistine
was evaluated after a single dose administration of betahistine in
male and female beagle dogs (age 5-7 months; weight of 5-11 kg,
within a range of 3 kg for each sex) for three routes of
administration: oral, intranasal, and intravenous.
[0220] On Day 1 of the study, betahistine (BH) was delivered orally
at a dose of 12 mg/kg, 24 mg/kg, or 48 mg/kg. Each treatment group
comprised 8 animals (4 males and 4 females). For pharmacokinetic
assessment, plasma samples were collected prior to dosing, and then
at 5, 10, 20 and 30 min, 1, 2, 3, 6, 24 hours after dosing.
[0221] On Day 8 of the study, the animals that received oral BH at
a dose of 12 mg/kg were administered the test betahistine
composition intranasally at a dose of 40 mg betahistine
dihydrochloride; the animals that received oral BH at a dose of 24
mg/kg were administered the test betahistine composition
intranasally at a dose of 80 mg betahistine dihydrochloride; and
the animals that received oral BH at a dose of 48 mg/kg were
administered the test betahistine composition intranasally at a
dose of 120 mg betahistine dihydrochloride. The test betahistine
composition was delivered intranasally in a single dose via an
Aptar nasal spray pump device at a total dose level of 40, 80 and
120 mg of betahistine dihydrochloride. Plasma samples were
collected prior to dosing, and then at 5, 10, 20 and 30 min, 1, 2,
3, 6, 24 hours after dosing.
[0222] On Day 15 of the study, the animals that received oral BH at
a dose of 12 mg/kg and the test betahistine composition
intranasally at a dose of 40 mg betahistine dihydrochloride were
administered a bolus intravenous injection of betahistine at a dose
of 0.44 mg/kg. Plasma samples were collected prior to dosing, and
then at 5, 10, 20 and 30 min, 1, 2, 3, 6, 24 hours after
dosing.
[0223] Plasma concentrations were measured with liquid
chromatographic tandem mass spectrometric method (LC-MS/MS; SCIEX
API 5000 for betahistine, SCIEX API 4000 for 2-Pyridylacetic Acid
(2-PAA)) with validated methods. Betahistine 13CD3 dihydrochloride
and 2-pyridylacetic acid-D.sub.4 hydrochloride were used as
respective internal standards. The calibration range for
betahistine was 0.05-250 ng/mL and for 2-PAA 2.00-3000 ng/mL using
a plasma sample volume of 0.50 mL.
[0224] For determination of betahistine, the method involved
liquid-liquid extraction, for 2-PAA, the method involved protein
precipitation. Plasma samples were prepared for betahistine by
extraction under basic conditions with an organic solvent, then the
organic phase was dried, reconstituted and transferred for LC/MS-MS
analysis. For 2-PAA, plasma samples were precipitated with a
mixture of organic solvents, the supernatant dried, reconstituted
and transferred for LC/MS-MS analysis. Sample analysis was
performed using reversed phase chromatography.
[0225] Intranasal administration of betahistine was well tolerated
in the dogs. In the highest concentration betahistine group
salivation was noted in most animals and sneezing occurred in 2/8
animals at that dose level.
[0226] Plasma levels of betahistine and 2-PAA in the study animals
were as shown in the Tables 9-17.
TABLE-US-00009 TABLE 9 Plasma levels of betahistine following
intranasal administration of test betahistine composition at a
total dose of 40, 80, and 120 mg of betahistine dihydrochloride
(values for male and female animals shown separately) Betahistine
Plasma Concentration (pg/mL) Male Female Male Female Male Female
Time (h) 40 mg 40 mg 80 mg 80 mg 120 mg 120 mg 0 0 54.25 29.25 0 90
25.5 0.08333333 469250 733750 606500 1639750 661750 1144000 0.167
440300 457750 619750 1178000 515250 825250 0.333 333883 295950
179300 605000 295000 244750 0.5 52123 15475 14540 50450 27175 31200
1 9045 5088 12143 20975 13060 16510 2 2319 879 546 8680 3718 5010 3
453 850 252 2078 945 1894 6 244 361 340 712 266 1118 24 221 96 67
189 288 314
TABLE-US-00010 TABLE 10 Plasma levels of betahistine following
intranasal administration of test betahistine composition at a
total dose of 40, 80, and 120 mg of betahistine dihydrochloride
(values for male and female animals pooled) Betahistine Plasma
Concentration (pg/mL) Time (h) 40 mg 80 mg 120 mg 0 27 15 58
0.08333333 601500 1123125 902875 0.167 449025 898875 670250 0.333
314916 392150 269875 0.5 33799 32495 29188 1 7066 16559 14785 2
1599 4613 4364 3 652 1165 1419 6 303 526 692 24 158 128 301
TABLE-US-00011 TABLE 11 Plasma levels of betahistine following oral
administration of betahistine at a dose of 12 mg/kg, 24 mg/kg, and
48 mg/kg (values for male and female animals shown separately)
Betahistine Plasma Concentration (pg/mL) Male Female Male Female
Male Female Time (h) 12 mg/kg 12 mg/kg 24 mg/kg 24 mg/kg 48 mg/kg
48 mg/kg 0 0 0 0 0 0 0 0.08333333 1.35 2588 4690 5316 14328 9873
0.167 2728 6465 5055 5238 35703 9243 0.333 5800 10113 23903 7133
14330 11483 0.5 18915 7798 17840 11983 33700 19350 1 5653 14058
26880 36825 80150 32825 2 457 263 2079 3578 21680 21325 3 36 0 611
1710 2997 10138 6 16 0 78 342 238 640 24 21 0 0 0 0 0
TABLE-US-00012 TABLE 12 Plasma levels of betahistine following oral
administration of betahistine at a dose of 12 mg/kg, 24 mg/kg, and
48 mg/kg (values for male and female animals pooled) Betahistine
Plasma Concentration (pg/mL) Time (h) 12 mg/kg 24 mg/kg 48 mg/kg 0
0 0 0 0.08333333 1969 5002.875 12100 0.167 4596.25 5146.25 22472.5
0.333 7956.25 15517.5 12906.25 0.5 13356.25 14911.25 26525 1 9855
31852.5 56487.5 2 359.88 2828 21503 3 18.1 1160.6 6567.1 6 7.975
210.1 438.99 24 10.4625 0 0
TABLE-US-00013 TABLE 13 Plasma levels of betahistine following
intravenous administration of betahistine at a dose of 0.44 mg/kg
(values for male and female animals shown separately) Betahistine
Plasma Concentration (pg/mL) Male 0.44 Female 0.44 Time (h) mg/kg
mg/kg 0 110 55.05 0.08333333 58175 43700 0.167 29100 14825 0.333
8063 5995 0.5 5568 4063 1 349 268 2 993 274 3 81 95 6 1051 648 24 0
405
TABLE-US-00014 TABLE 14 Plasma levels of betahistine following
intravenous administration of betahistine at a dose of 0.44 mg/kg
(values for male and female animals pooled) Betahistine Plasma
Concentration (pg/mL) Time (h) 0.44 mg/kg 0 82.525 0.08333333
50937.5 0.167 21962.5 0.333 7028.75 0.5 4815 1 308.375 2 633.34 3
87.75 6 849.25 24 202.25
TABLE-US-00015 TABLE 15 Plasma levels of 2-PAA following intranasal
administration of test betahistine composition at a total dose of
40, 80, and 120 mg of betahistine dihydrochloride (values for male
and female animals pooled) 2-PAA Plasma Concentration (ng/mL) Time
(h) 40 mg 80 mg 120 mg 0 1 3 3 0.08333333 350 422 482 0.167 1436
1414 1356 0.333 3242 2996 2424 0.5 4231 3531 2715 1 4101 5163 3835
2 2937 3345 2494 3 1676 2073 1499 6 382 424 318 24 8 13 15
TABLE-US-00016 TABLE 16 Plasma levels of 2-PAA following oral
administration of betahistine at a dose of 12 mg/kg, 24 mg/kg, and
48 mg/kg (values for male and female animals pooled) 2-PAA Plasma
Concentration (ng/mL) Time (h) 12 mg/kg 24 mg/kg 48 mg/kg 0 0 0 0
0.08333333 186.31625 266.46 233.64875 0.167 720.45 528.7875
694.2125 0.333 2492.75 2619.25 2298.75 0.5 5722.5 5121.25 5175 1
13236.3 17751.3 25963.8 2 11664 21963 39113 3 6443.8 14701 33845 6
1611.5 3966.3 10266 24 7.73125 13.7863 35.675
TABLE-US-00017 TABLE 17 Plasma levels of 2-PAA following
intravenous administration at a dose of 0.44 mg/kg (values for male
and female animals pooled) 2-PAA Plasma Concentration (ng/mL) Time
(h) 0.44 mg/kg 0 0.6088 0.08333333 652.875 0.167 709.875 0.333
633.375 0.5 583.75 1 513 2 286.13 3 164.75 6 36.475 24 2.1475
[0227] FIGS. 5 and 6 are graphs showing the median (FIG. 5) and
mean (FIG. 6) betahistine plasma concentrations following
intranasal administration of betahistine dihydrochloride at a total
dose of 40, 80, and 120 mg over time, with values for male and
female animals pooled. The graph based on the median values, FIG.
5, shows a dose-dependent increase in the betahistine plasma
concentration. In the graph based on the mean values (FIG. 6), the
mean C.sub.max for the 80 mg dose appears to be higher than the
mean C.sub.max for the 120 mg dose. This discrepancy is due to
certain outlier values.
[0228] FIGS. 7 and 8 are graphs showing the median (FIG. 7) and
mean (FIG. 8) betahistine plasma concentrations, with values for
male and female animals pooled, following oral administration of
betahistine over time.
[0229] FIGS. 9 and 10 are graphs showing the median (FIG. 9) and
mean (FIG. 10) betahistine plasma concentrations, with values for
male and female animals pooled, following intravenous
administration of betahistine over time.
[0230] Tables 18-20 show a summary of pharmacokinetic parameters
for betahistine (BH) following oral, intranasal, and intravenous
administration. Tables 21-23 show a summary of pharmacokinetic
parameters for 2-PAA following oral, intranasal, and intravenous
administration of betahistine.
TABLE-US-00018 TABLE 18 Summary (Mean .+-. SD) BH Pharmacokinetics
Parameters in Beagle Dog Plasma Following Oral Administration of BH
on Day 1 Dose C.sub.max/D AUC.sub.(0-6)/D (mg/ T.sub.max.sup.a
C.sub.max (ng/mL/ AUC.sub.(0-6) AUC.sub.(0-t) (hr*ng/mL/
AUC.sub.(0-inf) T.sub.1/2 Day Analyte Route Gender kg) (hr) (ng/mL)
(mg/kg)) (hr*ng/mL) (hr*ng/mL) (mg/kg)) (hr*ng/mL) (hr) 1 BH Oral
Male 12 0.5 18.9 .+-. 9.99 1.58 .+-. 0.833 13.0 .+-. 2.23 12.5 .+-.
2.02 1.04 .+-. 0.168 13.3 .+-. ID 0.313 .+-. (0.5-0.5) ID 24 1 38.3
.+-. 28.1 1.60 .+-. 1.17 34.5 .+-. 17.2 34.5 .+-. 17.1 1.44 .+-.
0.714 34.6 .+-. 17.1 0.785 .+-. (0.33-1) 0.388 48 1 102 .+-. 30.2
2.13 .+-. 0.628 131 .+-. 28.3 131 .+-. 28.3 2.73 .+-. 0.590 133
.+-. ID 0.522 .+-. (1-1) ID Female 12 1 14.7 .+-. 4.56 1.22 .+-.
0.380 NC 15.9 .+-. 5.80 1.33 .+-. 0.483 NC NC (0.5-1) 24 1 38.0
.+-. 26.1 1.58 .+-. 1.09 26.2 .+-. ID 41.0 .+-. 17.9 1.71 .+-.
0.748 27.7 .+-. ID 1.41 .+-. (0.33-1) ID 48 1 33.5 .+-. 9.11 0.697
.+-. 0.190 77.5 .+-. 25.4 77.5 .+-. 25.4 1.61 .+-. 0.528 69.2 .+-.
23.3 0.599 .+-. (0.08-1) 0.0351 Sex- 12 0.5 16.8 .+-. 7.54 1.40
.+-. 0.628 13.0 .+-. 2.23 14.2 .+-. 4.41 1.18 .+-. 0.368 13.3 .+-.
ID 0.313 .+-. Combined (0.5-1) ID 24 1 38.2 .+-. 25.1 1.59 .+-.
1.05 31.7 .+-. 14.0 37.8 .+-. 16.6 1.57 .+-. 0.692 32.3 .+-. 13.8
0.995 .+-. (0.33-1) 0.458 48 1 62.9 .+-. 41.2 1.31 .+-. 0.857 100
.+-. 37.6 100 .+-. 37.6 2.09 .+-. 0.783 94.6 .+-. 43.4 0.568 .+-.
(0.08-1) 0.0565 .sup.aMedian T.sub.max (Min-Max); NC = Not
Calculated; ID = Insufficient Data.
TABLE-US-00019 TABLE 19 Summary (Mean .+-. SD) BH Pharmacokinetics
Parameters in Beagle Dog Plasma Following Intranasal Administration
of BH (AM-125) on Day 8 Nominal Dose C.sub.max/D AUC.sub.(0-t)/D
AUC.sub.(0-inf) Dose (mg/ T.sub.max.sup.a C.sub.max (ng/mL/
AUC.sub.(0-6) AUC.sub.(0-t) (hr*ng/mL/ (hr*ng/ T.sub.1/2 Day
Analyte Route Gender (mg) kg) (hr) (ng/mL) (mg/kg)) (hr*ng/mL)
(hr*ng/mL) (mg/kg)) mL) (hr) 8 BH Intra- Male 40 5 0.17 598 .+-.
120 .+-. 90.1 178 .+-. 122 182 .+-. 122 36.4 .+-. 24.4 131 .+-. ID
NM nasal (0.08-0.33) 451 80 9.8 0.13 735 .+-. 75.0 .+-. 56.9 168
.+-. 140 172 .+-. 140 17.5 .+-. 14.3 202 .+-. 156 NM (0.08-0.17)
557 120 15.8 0.13 765 .+-. 48.4 .+-. 23.7 194 .+-. 79.8 199 .+-.
78.5 12.6 .+-. 4.97 NC NC (0.08-0.17) 375 Female 40 6 0.08 770 .+-.
128 .+-. 42.1 180 .+-. 57.3 181 .+-. 55.8 30.2 .+-. 9.31 NC NC
(0.08-0.17) 253 80 13 0.14 1790 .+-. 138 .+-. 102 432 .+-. 281 440
.+-. 283 33.8 .+-. 21.8 480 .+-. 336 NM (0.08-0.33) 1320 120 17.7
0.08 1330 .+-. 75.1 .+-. 17.0 277 .+-. 7.99 290 .+-. 8.47 16.4 .+-.
0.479 302 .+-. ID NM (0.08-0.17) 300 .sup.aMedian T.sub.max
(Min-Max); NM = Not Meaningful; NC = Not Calculated; ID =
Insufficient Data.
TABLE-US-00020 TABLE 20 Summary (Mean .+-. SD) BH Pharmacokinetics
Parameters in Beagle Dog Plasma Following IV Bolus Injection of BH
on Day 15 C.sub.max/D AUC.sub.(0-6) AUC.sub.(0-t) AUC.sub.(0-t)/D
AUC.sub.(0-inf) CL Dose T.sub.max.sup.a C.sub.max (ng/mL/ (hr*ng/
(hr*ng/ (hr*ng/mL/ (hr*ng/ T.sub.1/2 (mL/hr/ Vd Day Analyte Route
Gender (mg/kg) (hr) (ng/mL) (mg/kg)) mL) mL) (mg/kg)) mL) (hr) kg)
(mL/kg) 15 BH IV Male 0.44 0.08 58.2 .+-. 132 .+-. 19.5 .+-. 19.5
.+-. 44.3 .+-. 11.5 18.4 .+-. ID 0.930 .+-. 23900 .+-. 32100 .+-.
Bolus (0.08-0.08) 7.93 18.0 5.05 5.06 ID ID ID Female 0.44 0.09
43.7 .+-. 99.3 .+-. 16.3 .+-. 26.5 .+-. 60.3 .+-. 40.0 14.3 .+-. ID
0.238 .+-. 30800 .+-. 10600 .+-. (0.08-0.11) 8.84 20.1 6.54 17.6 ID
ID ID Sex- 0.44 0.08 50.9 .+-. 116 .+-. 17.9 .+-. 23.0 .+-. 52.3
.+-. 28.5 16.3 .+-. ID 0.584 .+-. 27400 .+-. 21300 .+-. Combined
(0.08-0.11) 11.0 24.9 5.67 12.6 ID ID ID .sup.aMedian T.sub.max
(Min-Max); ID = Insufficient Data.
TABLE-US-00021 TABLE 21 Summary (Mean .+-. SD) 2-PAA
Pharmacokinetics Parameters in Beagle Dog Plasma Following Oral
Administration of BH on Day 1 C.sub.max/D AUC.sub.(0-t)/D Dose
T.sub.max.sup.a C.sub.max (ng/mL/ AUC.sub.(0-6) AUC.sub.(0-t)
(hr*ng/mL/ AUC.sub.(0-int) T.sub.1/2 Day Analyte Route Gender
(mg/kg) (hr) (ng/mL) (mg/kg)) (hr*ng/mL) (hr*ng/mL) (mg/kg))
(hr*ng/mL) (hr) 1 2-PAA Oral Male 12 1.5 12700 .+-. 1060 .+-. 37300
.+-. 50500 .+-. 21100 4210 .+-. 1760 50500 .+-. 21100 2.21 .+-.
0.160 (1-2) 2420 202 10500 24 1.5 26400 .+-. 1100 .+-. 76400 .+-.
107000 .+-. 28200 4460 .+-. 1180 107000 .+-. 28200 2.04 .+-. 0.107
(1-2) 7520 313 21100 48 2 50900 .+-. 1060 .+-. 178000 .+-. 286000
.+-. 39200 5950 .+-. 817 286000 .+-. 39300 2.10 .+-. 0.181 (2-2)
8840 184 24900 Female 12 1 14500 .+-. 1210 .+-. 41300 .+-. 57200
.+-. 11300 4760 .+-. 940 57200 .+-. 11300 2.12 .+-. 0.110 (1-2)
1370 114 5020 24 2 21300 .+-. 885 .+-. 69300 .+-. 110000 .+-. 14300
4590 .+-. 594 110000 .+-. 14300 2.14 .+-. 0.176 (1-2) 3530 147 7850
48 2 37500 .+-. 781 .+-. 144000 .+-. 237000 .+-. 63500 4930 .+-.
1320 208000 .+-. 35000 2.24 .+-. 0.170 (2-3) 8560 178 35400 Sex- 12
1 13600 .+-. 1130 .+-. 39300 .+-. 53800 .+-. 16000 4490 .+-. 1340
53900 .+-. 16100 2.17 .+-. 0.135 Combined (1-2) 2060 172 7930 24 2
23800 .+-. 992 .+-. 72900 .+-. 109000 .+-. 20800 4530 .+-. 866
109000 .+-. 20800 2.09 .+-. 0.145 (1-2) 6090 254 15200 48 2 43200
.+-. 901 .+-. 158000 .+-. 258000 .+-. 56700 5370 .+-. 1180 247000
.+-. 53900 2.17 .+-. 0.176 (2-3) 10700 222 34200 .sup.aMedian
T.sub.max (Min-Max).
TABLE-US-00022 TABLE 22 Summary (Mean .+-. SD) 2-PAA
Pharmacokinetics Parameters in Beagle Dog Plasma Following
Intranasal Administration of BH on Day 8 Nominal C.sub.max/D
AUC.sub.(0-t)/D Dose Dose T.sub.max.sup.a C.sub.max (ng/mL/
AUC.sub.(0-6) AUC.sub.(0-t) (hr*ng/mL/ AUC.sub.(0-inf) T.sub.1/2
Day Analyte Route Gender (mg) (mg/kg) (hr) (ng/mL) (mg/kg))
(hr*ng/mL) (hr*ng/mL) (mg/kg)) (hr*ng/mL) (hr) 8 2-PAA Intra- Male
40 5 0.5 3480 .+-. 695 .+-. 9440 .+-. 12200 .+-. 2440 .+-. 2160
12200 .+-. 2.96 .+-. nasal (0.5-1) 2270 454 7580 10800 10800 0.536
80 9.8 1 3320 .+-. 339 .+-. 8450 .+-. 10400 .+-. 1060 .+-. 368
10400 .+-. 2.86 .+-. (0.5-1) 1070 109 2870 3600 3610 0.186 120 15.8
1 3930 .+-. 249 .+-. 10200 .+-. 12700 .+-. 806 .+-. 197 12800 .+-.
2.87 .+-. (0.33-1) 987 62.5 2640 3110 3090 0.434 Female 40 6 0.75
5570 .+-. 928 .+-. 14800 .+-. 19000 .+-. 3170 .+-. 812 19000 .+-.
2.66 .+-. (0.5-1) 1290 215 3710 4870 4860 0.275 80 13 1 7030 .+-.
541 .+-. 19300 .+-. 25200 .+-. 1940 .+-. 838 25300 .+-. 2.97 .+-.
(1-1) 3020 232 7760 10900 10900 0.348 120 17.7 1 3810 .+-. 215 .+-.
10600 .+-. 14000 .+-. 790 .+-. 307 14100 .+-. 3.46 .+-. (1-2) 765
43.2 3470 5440 5470 0.239 .sup.aMedian T.sub.max (Min-Max).
TABLE-US-00023 TABLE 23 Summary (Mean .+-. SD) 2-PAA
Pharmacokinetics Parameters in Beagle Dog Plasma Following IV Bolus
Injection of BH on Day 15 Dose C.sub.max/D AUC.sub.(0-t)/D (mg/
T.sub.max.sup.a C.sub.max (ng/mL/ AUC.sub.(0-6) AUC.sub.(0-t)
(hr*ng/mL/ AUC.sub.(0-inf) T.sub.1/2 Day Analyte Route Gender kg)
(hr) (ng/mL) (mg/kg)) (hr*ng/mL) (hr*ng/mL) (mg/kg)) (hr*ng/mL)
(hr) 15 2-PAA IV Male 0.44 0.13 736 .+-. 53.5 1670 .+-. 121 1450
.+-. 388 1740 .+-. 641 3960 .+-. 1460 1760 .+-. 642 2.59 .+-. Bolus
(0.08-0.33) 1.07 Female 0.44 0.18 722 .+-. 75.3 1640 .+-. 171 1540
.+-. 101 1830 .+-. 209 4160 .+-. 475 1860 .+-. 188 2.78 .+-.
(0.11-0.2) 1.01 Sex- 0.44 0.17 729 .+-. 60.9 1660 .+-. 138 1500
.+-. 267 1790 .+-. 444 4060 .+-. 1010 1810 .+-. 441 2.69 .+-.
Combined (0.08-0.33) 0.968 .sup.aMedian T.sub.max (Min-Max).
[0231] Tables 24 and 25 show the Absolute Bioavailability (% F) of
betahistine (BH) in dogs following oral and intranasal
administration.
TABLE-US-00024 TABLE 24 Absolute Bioavailability (% F) of BH in
Beagle Dog Plasma Following Oral Administration of BH Route Dose %
F Comparison Analyte Gender (mg/kg) AUC.sub.(0-t)/D Oral/IV Bolus
BH Male 12/0.44 2.35 24/0.44 3.24 48/0.44 6.17 Female 12/0.44 2.20
24/0.44 2.84 48/0.44 2.68 Sex-Combined 12/0.44 2.26 24/0.44 3.01
48/0.44 4.01
TABLE-US-00025 TABLE 25 Absolute Bioavailability (%) of BH in
Beagle Dog Plasma Following Intranasal Administration of BH Route
Dose % F Comparison Analyte Gender (mg/kg) AUC.sub.(0-t)/D
Intranasal/ BH Male 5/0.44 82.1 IV Bolus 9.8/0.44 39.5 15.8/0.44
28.4 Female 6/0.44 50.2 13/0.44 56.1 17.7/0.44 27.1
[0232] Table 26 shows the Relative Bioavailability (Frel) of
betahistine (BH) administered intranasally relative to the oral
administration.
TABLE-US-00026 TABLE 26 Bioavailability of betahistine in dogs for
intranasal administration relative to oral administration
Intranasal Oral AUC/dose AUC/dose Dose Dose (h ng/mL)/ (h ng/mL)/
Rel. (mg) (mg/kg) (mg/kg) mg/kg (mg/kg) Bioavail. Dogs, male 40 5
36.4 12 1.04 35.0 80 9.8 17.5 24 1.44 12.2 120 15.8 12.6 48 2.73
4.6 Dogs, female 40 6 30.2 12 1.33 22.7 80 13 33.8 24 1.71 19.8 120
17.7 16.4 48 1.61 10.2
Example 6: Relative Bioavailability of Betahistine Via Intranasal
Administration Relative to Oral Administration in Humans
[0233] For the calculation of the relative bioavailability of
intranasal betahistine compared to peroral betahistine, the area
under the concentration-time curve (AUC) determined in Example 3
was compared to the AUC determined in a study with oral betahistine
in healthy volunteers described in Barak et al. (Journal of
Psychopharmacology, 2016, Vol. 30(3) 237-241). In brief, in this
study, forty-eight healthy women were recruited and randomized to
receive per os (i.e. orally) either betahistine 144 mg/day (48 mg
t.i.d.) or matching placebo for 4 weeks. Their mean weight was 60.2
kg in the active-treated group (n=24) and 59.8 kg in the placebo
group (n=24). Study medication (betahistine or matching placebo)
was administered at least 30 minutes prior to eating. On Day 8,
blood samples of 6 mL each were collected at 8 am, and 30, 60, 150
and 300 minutes thereafter. Plasma concentrations of betahistine
and its metabolite 2-PAA were determined by high-performance
liquidy chromatography. The AUC.sub.(0-5h) was 121 pgh/mL at a dose
of approximately 0.8 mg/kg.
[0234] For an intranasal dose of 40 mg (or 0.57 mg/kg) in Example
3, an AUC of 3531 pgh/mL resulted (see Table 3).
[0235] Based on the AUC values for oral administration in the Barak
et al. study and the AUC values for intranasal administration from
Example 3, a relative bioavailability of oral vs. intransal (i.e.
bioavailability via oral relative to intranasal) administration
comes out to be approximately 2.4% whereas the relative
bioavailability of intranasal vs oral (bioavailability via
intranasal relative to oral) is summarized in the following
table.
TABLE-US-00027 TABLE 27 Bioavailability of betahistine via
intranasal administration relative to oral administration AUC/ AUC
Dose Dose Weight Dose (h*ng/ (h ng/mL)/ Rel. (mg) (kg) (mg/kg) mL)
(mg/kg) Bioavail. Barak et al. data (oral) 48 60.2 0.8 0.121 0.15
Example 3 data (intranasal) 5 71.9 0.07 0.209 3.01 19.9 10 68.8
0.15 0.533 3.67 24.2 20 69.6 0.29 1.608 5.60 37.0 40 70.4 0.57
3.531 6.21 41.1
[0236] Table 27 shows that the bioavailability with intranasal
administration is 20-40 times higher than with oral administration.
When using relative bioavailability at comparable absolute
doses--40 mg intranasal vs. 48 mg per os--the fold factor is
41.1.times.. The 0.8 mg/kg in the Barak et al. study represent the
currently approved 48 mg daily dose in one single administration;
although patients there received 3.times.48 mg daily, each dose is
considered separate due to the rapid elimination.
INCORPORATION BY REFERENCE
[0237] All references, articles, publications, patents, patent
publications, and patent applications cited herein are incorporated
by reference in their entireties for all purposes. However, mention
of any reference, article, publication, patent, patent publication,
and patent application cited herein is not, and should not be taken
as an acknowledgment or any form of suggestion that they constitute
valid prior art or form part of the common general knowledge in any
country in the world.
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