Note: Descriptions are shown in the official language in which they were submitted.
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TETRACAINE-BASED ANESTHETIC
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. provisional application
62/096,287, filed on December 23, 2014, which is hereby incorporated by
reference in its entirety.
TECHNICAL FIELD OF INVENTION
[0002] The present invention relates to tetracaine based anesthetic
formulations
and methods of use thereof. The present invention also relates to tetracaine
based
dental anesthetic formulations and methods for anesthetizing the upper back
molars, including the distal half of the first molar, second and third molars
of the
maxillary dental arch and the tissues around the back molars.
BACKGROUND OF THE INVENTION
[0003] The most common means for anesthetizing maxillary second and third
molars is through the use of an infiltration injection. For example, the
patient may
receive a needle penetration and injection of a local anesthetic solution at
the
approximate apex of the root(s) on the buccal surface of a tooth (or teeth) to
be
treated (e.g., filled or extracted). A maxillary palatal injection of dental
local
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anesthetic can be used for regional block anesthesia of teeth and/or in order
to
effect regional nerve blocks.
[0004] Dental anxiety, including needle or shot discomfort and phobia, is a
long-
standing barrier to regular dental care. In a survey conducted by the American
Dental Association, 27% of the people surveyed indicated "fear of pain" as a
reason to avoid dental visits. Needle injection of local anesthetic is
recognized as
the most anxiety-provoking procedure in dentistry for children and adults. Not
only can the injection of local anesthetics produce fear, pain and an increase
in
blood pressure, but the increased stress of injection can result in fainting,
hyperventilation, convulsions, shock, hypertension, cardiac arrest,
respiratory -
collapse, acute allergic reaction to preservatives, bronchospasm, angina, and
organ
system toxicity in medically compromised patients. Further, local injections
into
target nerves can sometimes lead to permanent numbness as a result of needles
damaging and/or cutting nerves. In rare cases, a severe overdose of injectable
anesthetic or accidental, rapid intravascular injection of the anesthetic can
even
lead to death. The act of injecting is invasive (conceptually,
psychologically, and
physically) and is a major reason worldwide why people avoid regular dental
care
and see their dentists only in an emergency. In fact, some studies indicate
that
millions of people in the US are afraid of dental treatments because of pain.
Without regular dental care, tooth caries, gum disease and oral cancer may be
left
undetected and can result in infection and serious, systemic health issues.
[0005] In addition, the risk of exposure to bloodborne pathogens via
needlesticks
is a recognized occupational hazard in dentistry. Since 1991, the Occupational
Safety and Health Administration ("OSHA") has enforced a Bloodborne Pathogens
Standard that requires employers to identify, evaluate and implement safer
medical
devices to eliminate or minimize employee exposure to bloodborne pathogens.
The standard was revised in 2000 when Congress passed the Needlestick Safety
and Prevention Act. The Act set forth in greater detail employers' obligations
under the Bloodborne Pathogens standard and specifically indicated that a
"safer
medical device" includes needleless systems. Thus, further incentive exists to
develop anesthetics that can be delivered without the use of needles and
comply
with U.S. federally mandated engineered work practice controls.
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[0006] Lidocaine, the most widely used local dental anesthetic today, was
first
introduced in the 1940s. Despite many attempts at developing needle-free
anesthetic, the only widely-used non-injectable, subsurface topical local
anesthetic
commercially available today is Oraqix gel. While Oraqix can be used in
periodontal pockets during scaling or root-planing procedures, it does not
provide
adequate anesthesia for use in procedures such as fillings, crowns and root
canals.
Moreover, intranasal administration of lidocaine to rats has been linked to
the
possible promotion of nasal carcinoma. Tyden et al., "Metabolic activation of
2,6-
xylidine in the nasal olfactory mucosa and the mucosa of the upper alimentary
and
respiratory tracts in rats," Toxicol. Sci., 81(2):263-72 (2004).
[0007] Further, while many advances in the comfort of dentistry have been
made,
such as behavior modification therapy, topical numbing around the injection
site,
nitrous oxide, hypnosis, and Transcutaneous Electrical Nerve Stimulation
("TENS") units, none of these advances has eliminated the need for needle
injection.
[0008] Thus, there remains a need for alternative and effective anesthetics.
In
particular, there remains a need for alternative and effective anesthetics and
means
for administering such anesthetics to a patient in order to anesthetize the
patient's
maxillary back molars, including the distal half of the first molar, second
and third
molars without creating extra oral soft tissue numbness, discomfort, or phobia
in
the patient.
SUMMARY OF THE INVENTION
[0009] The present invention provides a tetracaine based anesthetic and
methods
of use thereof.
[0010] In one aspect, the present invention provides a tetracaine based dental
anesthetic formulation, which can be administered nasally, and is useful for
anesthetizing the maxillary back molars, including the distal half of the
first molar,
second and third molars. In some embodiments, the invention is useful for
anesthetizing the maxillary second and third molars. The invention is based on
delivering anesthetic to specific areas in the nasal cavity and in or near the
nasal
sinuses, such as the maxillary sinus. The invention is also based on
delivering the
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anesthetic to the superior dental plexus, the infra-orbital branch of the
maxillary
nerve, the posterior superior alveolar nerve, the sphenopalatine
(pterygopalatine)
ganglion, the nerves under the Schneiderian membrane, and/or the
pterygopalatine
fossa (sphenopalatine fossa).
100111 The nerves of the upper teeth extend in and around the nasal cavity
area
down into the teeth. The pharmaceutical composition of the present invention
is
administered throughout the nasal cavity, affecting the nerve pathways at the
point
of contact and migrating superiorly, laterally, and inferiorly through the
maxilla.
This anesthetizes the branches that transmit nerve impulses from all of the
upper
teeth and surrounding tissue, including but not limited to superior dental
plexus
and the posterior superior alveolar nerve.
[0012] In one aspect, the invention provides a pharmaceutical composition
comprising a) tetracaine, or a pharmaceutically acceptable salt thereof; b) a
vasoconstrictor; and c) a pharmaceutically acceptable carrier. In other
embodiments, the pharmaceutical composition comprises a) tetracaine, or a
pharmaceutically acceptable salt thereof; b) a vasoconstrictor; c) a
preservative; d)
a viscosity enhancing agent; and e) a pharmaceutically acceptable carrier. In
some
embodiments, the composition comprises about 2.0-5.0% (w/v) tetracaine. In
some embodiments, the composition comprises about 2.25-4.75% (w/v) tetracaine.
In other embodiments, the composition comprises about 2.5-4.0% (w/v)
tetracaine.
In yet other embodiments, the composition comprises about 2.5-3.5% (w/v)
tetracaine. In other embodiments, the composition comprises about 3% (w/v)
tetracaine. In some embodiments, the pharmaceutical composition is for
intranasal
administration.
[0013] In one aspect, the invention provides a pharmaceutical composition
comprising a) tetracaine HC1; b) a vasoconstrictor; and c) a pharmaceutically
acceptable carrier. In other embodiments, the pharmaceutical composition
comprises a) tetracaine HC1; b) a vasoconstrictor; c) a preservative; d) a
viscosity
enhancing agent; and e) a pharmaceutically acceptable carrier. In some
embodiments, the composition comprises about 2.0-5.0% (w/v) tetracaine HCI. In
some embodiments, the composition comprises about 2.25-4.75% (w/v) tetracaine
HC1. In other embodiments, the composition comprises about 2.5-4.0% (w/v)
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tetracaine HCI. In yet other embodiments, the composition comprises about 2.5-
3.5% (w/v) tetracaine HCI. In other embodiments, the composition comprises
about 3% (w/v) tetracaine HCI. In some embodiments, the pharmaceutical
composition is for intranasal administration.
[0014] The vasoconstrictors that may be included in the pharmaceutical
compositions of the invention include, but are not limited to, sympathomimetic
agents, indirect ai-adrenergic; calcium channel blockers; meperidine;
imidazole
drugs such as oxymetazoline, xylometazoline, and dexmedetomidine;
a2-adrenergic agonists such as guanfacine; imidazoline (Ii) ligands; direct a2-
adrenergic agonists such as clonidine; substance P blockers/reducers such as
capsaicin; I-menthol; icilin; epinephrine (i.e., adrenaline); levonordefrin
(i.e.,
nordefrin); and glutamate receptor inhibitors; or pharmaceutically acceptable
salts
thereof. In some embodiments, the vasoconstrictor is oxymetazoline, or a
pharmaceutically acceptable salt thereof. In other embodiments, the
oxymetazoline is an oxymetazoline HCI salt.
[0015] In some embodiments, the pharmaceutical composition comprises about
0.01-1.0% (w/v) oxymetazoline HCI. In other embodiments, the pharmaceutical
composition comprises about 0.05-1.0% (w/v) oxymetazoline HCI. In other
embodiments, the pharmaceutical composition comprises about 0.05% (w/v)
oxymetazoline HCI.
[0016] In some embodiments, the pharmaceutical composition further comprises
a preservative. In some embodiments, the preservative includes, but is not
limited
to, sugar alcohols (e.g., sorbitol and mannitol), ethanol, benzyl alcohol,
isopropanol, cresol, chlorocresol, and phenol. In some embodiments, the
preservative is benzyl alcohol. In some embodiments, the pharmaceutical
composition comprises about 0.5-2.0% (w/v) benzyl alcohol. In other
embodiments, the pharmaceutical composition comprises about 0.9% (w/v) benzyl
alcohol.
[0017] In some embodiments, the pharmaceutical composition further comprises
a viscosity enhancing agent. Viscosity enhancing agents can also function as
tissue
penetration enhancing agents. In some embodiments, the viscosity enhancing
agent includes, but is not limited to methylcellulose, hydroxyethylcellulose,
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hydroxypropylmethylcellulose and smart hydrogel. In some embodiments, the
viscosity enhancing agent is hydroxyethylcellulose. In some embodiments, the
pharmaceutical composition comprises about 0.01-1.0% (w/v)
hydroxyethylcellulose. In other embodiments, the pharmaceutical composition
comprises about 0.05% (w/v) hydroxyethylcellulose.
[0018] In some embodiments, the pharmaceutical composition is formulated as a
gel, liquid or powder. In some embodiments the liquid is water, a sugar
alcohol, an
alcohol (e.g., ethanol), or any other anesthetic solvent that is biologically
compatible with the target tissue.
[0019] In some embodiments, the pH of the pharmaceutical composition is
between about 4.0 to about 7.5. In other embodiments, the pH of the
pharmaceutical composition is between about 4.0 to about 6.5. In another
embodiment the pharmaceutical composition has a pH of about 5.5 to about 6.5.
In
further embodiments, the pharmaceutical composition has a pH of about 6.0 to
about 6.5.
[0020] In a particular embodiment, the pharmaceutical composition comprises
tetracaine, oxymetazoline and benzyl alcohol. In another particular
embodiment,
the pharmaceutical composition comprises tetracaine HCI, oxymetazoline HCI,
and
benzyl alcohol. In another embodiment, the pharmaceutical composition
comprises tetracaine HCI, oxymetazoline HCI, anhydrous citric acid (for pH
control), sodium hydroxide (for pH adjustment), benzyl alcohol, hydrochloric
acid
(for pH control), hydroxyethylcellulose, and purified water. In yet another
embodiment, the pharmaceutical composition comprises tetracaine HCI,
oxymetazoline HCI, anhydrous citric acid (for pH control), anhydrous sodium
citrate (for pH control), sodium hydroxide (for pH adjustment), benzyl
alcohol,
hydrochloric acid (for pH control), hydroxyethylcellulose, and purified water.
In
another embodiment, the pharmaceutical composition comprises tetracaine HCI,
oxymetazoline HCI, anhydrous citric acid (for pH control), sodium citrate
dihydrate (for pH control), sodium hydroxide (for pH adjustment), benzyl
alcohol,
hydrochloric acid (for pH control), hydroxyethylcellulose, and purified water.
In a
more particular embodiment, the pharmaceutical composition of the present
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invention comprises the components, and respective amounts, listed in Table 1
below (referred to herein as the "Table 1 formulation").
Table 1
/111#
lgi-edient - ''il '47, FOritiThia t ion CV0 w/Vt, "
. ,--
I etritcaine hydrochloride, l_ESPI', 00
.I., 0 I=v7iiie.1773lirielh73,711767c1i1:6A10 :'I:=- US I' = -II ''' 0' 0
', -
Citric acid anhydrous, USP 0 05S
USP So,dirrthriratgrArdtpuS';I 27
,t 'Mlirinirgifat7eTaifile.Si7,%,SF'. ' - I' 44 ::f..,:
Sodium hydroxide, NF q s
Un4l ilEolUINFII "II-I` 0 00 Ii"
Hydrochloric acid, NF q s
irlysk¨prwommirilase;NF,, .. - - ' 0 0 5
Purified water, USP q.s. to 100 mL
[0021] In another aspect, the invention provides a method for anesthetizing
the
maxillary back molars, including the distal half of the first molar, second
and third
molars (and pain fibers external to the dental arch) in a subject comprising
selectively delivering near or in the nasal cavity of the subject a
pharmaceutical
composition of the invention, wherein at least a portion of the pharmaceutical
composition is absorbed by nasal tissue located at the rear of the nasal
cavity in the
vicinity of the sphenopalatine ganglion, the posterior superior alveolar
nerve, the
superior dental plexus, the infra-orbital branch of the maxillary nerve, the
nerves
under the Schneiderian membrane, and/or the pterygopalatine fossa
(sphenopalatine fossa). In some embodiments, the invention provides a method
for
anesthetizing the maxillary second and third molars (and pain fibers external
to the
dental arch) in a subject comprising selectively delivering near or in the
nasal
cavity of the subject a pharmaceutical composition of the invention, wherein
at
least a portion of the pharmaceutical composition is absorbed by nasal tissue
located at the rear of the nasal cavity in the vicinity of the sphenopalatine
ganglion,
the posterior superior alveolar nerve, the superior dental plexus, the infra-
orbital
branch of the maxillary nerve, the nerves under the Schneiderian membrane,
and/or
the pterygopalatine fossa (sphenopalatine fossa). This method anesthetizes the
maxillary back molars (and relevant pain fibers outside, but around, the
maxillary
arch) of the subject. In some embodiments, the pharmaceutical composition is
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delivered into the nasal sinus and/or rear of the nasal cavity of the subject.
In some
embodiments, the tissues around the maxillary back molars are also
anesthetized.
In other embodiments, the tissues around the maxillary second and third molars
are
also anesthetized. In some embodiments, the pharmaceutical composition is
delivered by nebulization, ionophoresis, laser, ultrasound (typically at
greater than
20,000 cycles/second) or spraying. In some embodiments the pharmaceutical
composition is chilled or heated before administration. In some embodiments,
the
pharmaceutical composition is delivered by spraying. In other embodiments, the
delivered spray is a stream or a plume. In some embodiments, the method is for
anesthetizing the back molars, including the distal half of the first molar,
second
and third molars. In other embodiments, the method is for anesthetizing the
maxillary second and third molars.
100221 In some embodiments, the method comprises spraying the intranasal
pharmaceutical composition of the invention several times into each of the
nostrils
of the subject. In some embodiments, the method comprises spraying the
intranasal pharmaceutical composition of the invention 1-5 times into each of
the
nostrils of the subject. In some embodiments, the method comprises spraying
the
intranasal pharmaceutical composition of the invention 1-3 times into each of
the
nostrils of the subject. In other embodiments, the method comprises spraying
the
pharmaceutical composition of the invention 3 times into each of the nostrils
of the
subject. In some embodiments, the method comprises spraying the pharmaceutical
composition of the invention 1-5 times into one of the nostrils of the
subject. In
some embodiments, the method comprises spraying the pharmaceutical
composition of the invention 1-3 times into one of the nostrils of the
subject. In
other embodiments, the method comprises spraying the pharmaceutical
composition of the invention 3 times into one of the nostrils of the subject.
In
some embodiments, each of the sprays are administered within about 1-10
minutes,
of each other. For example, spray #1 may be administered, followed by an
interval
of about 1-10 minutes, after which spray #2 is administered, followed by an
interval of about 1-10 minutes after which spray #3 is administered, etc. In
some
embodiments, the interval between sprays is about 1-6 minutes. In some
embodiments, the interval between sprays is about 2-6 minutes. In other
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embodiments, the interval between sprays is about 3-5 minutes. In yet other
embodiments, the interval between sprays is about 4 minutes.
[0023] In some embodiments, the method comprises delivering a known (e.g.,
metered) amount of tetracaine near or in the nasal cavity of the subject. In
some
embodiments, the method comprises delivering about 12-50 mg of tetracaine into
the nasal sinuses and/or rear of the nasal cavity of the subject. In other
embodiments, the method comprises delivering about 15-24 mg of tetracaine into
the nasal sinuses and/or rear of the nasal cavity of the subject. In another
embodiment, the method comprises delivering about 15-20 mg of tetracaine into
the nasal sinuses and/or rear of the nasal cavity of the subject. In another
embodiment, the method comprises delivering about 18 mg of tetracaine into the
nasal sinuses and/or rear of the nasal cavity of the subject.
[0024] In some embodiments, the method comprises delivering a known (e.g.,
metered) amount of tetracaine HC1 near or in the nasal cavity of the subject.
In
some embodiments, the method comprises delivering about 12-50 mg of tetracaine
HC1 into the nasal sinuses and/or rear of the nasal cavity of the subject. In
other
embodiments, the method comprises delivering about 15-24 mg of tetracaine HC1
into the nasal sinuses and/or rear of the nasal cavity of the subject. In
another
embodiment, the method comprises delivering about 15-20 mg of tetracaine HC1
into the nasal sinuses and/or rear of the nasal cavity of the subject. In
another
embodiment, the method comprises delivering about 18 mg of tetracaine HC1 into
the nasal sinuses and/or rear of the nasal cavity of the subject.
[0025] In some embodiments, the particle size of the pharmaceutical
composition
delivered to the rear of the nasal sinuses and/or rear of the nasal cavity is
about 5-
50 microns ( m). In other embodiments, the particle size of the pharmaceutical
composition is about 10-20 microns. In other embodiments, the pharmaceutical
composition is delivered in a manner such that at least 85% of the particles
are at
least about 10 microns or larger. In yet other embodiments, the particle size
of the
pharmaceutical composition is about 10 microns or larger.
[0026] In another aspect, the invention provides a spray device for intranasal
delivery of a pharmacputical composition of the present invention. In some
embodiments, the spray device is capable of delivering the intranasal
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pharmaceutical composition to the nasal tissue located at the rear of the
nasal
cavity. In other embodiments, the spray device is capable of delivering the
intranasal pharmaceutical composition to the nasal tissue located in the nasal
sinuses and at the rear of the nasal cavity, in the vicinity of the superior
dental
plexus, the infra-orbital branch of the maxillary nerve, the posterior
superior
alveolar nerve, the sphenopalatine (pterygopalatine) ganglion, the nerves
under the
Schneiderian membrane, and/or the pterygopalatine fossa (sphenopalatine
fossa)..
In yet other embodiments, the spray device is pre-filled with an intranasal
pharmaceutical composition of the present invention.
BRIEF DESCRIPTION OF THE FIGURES
10027] Figure 1 is a cross-sectional side view of a person's nasal cavity,
maxillary dentition and associated nerves. Both the greater and lesser
palatine
nerves originate at the pterygopalatine (sphenopalatine) ganglion. The
superior
dental plexus, and anterior, middle and posterior superior alveolar nerves
connect
together and originate at the maxillary nerve. The maxillary nerve
communicates
with the fibers of the trigeminal ganglion to the fifth cranial nerve where it
exits
from the foramen rotundum. The nasopalatine branch of the anterior superior
alveolar nerve connects between the alveolar nerves and the palatine nerves.
The
anterior and posterior superior alveolar nerves connect in the superior dental
plexus. The nerve endings of the anterior superior alveolar nerve are located
in the
front teeth (i.e., the anterior teeth, first and second bicuspids, and mesial
half of the
first molar). The nerve endings of the middle superior alveolar nerve, when
present, are located in the middle teeth (i.e., the first and second maxillary
premolars, mesial half of the maxillary first molar, mesial half of the first
molars,
and upper first and second bicuspids on both sides of the maxillary arch). The
nerve endings of the posterior superior alveolar nerve are located in the rear
teeth
(i.e., the first and second maxillary premolars and the maxillary first,
second, and
third molars). These nerves and the preceding nerves (which are joined in the
trigeminal ganglion where the maxillary nerve meets the other branches of the
fifth
cranial nerve) are primarily responsible for the transmission of pain impulses
from
the teeth to the brain. The greater palatine nerve, whose nerve endings are in
the
hard, is responsible (along with the preceding nerves) for the transmission of
pain
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impulses from the hard and soft palate to the brain. Similarly, the lesser
palatine
nerve, whose nerve endings are in the soft palate, is responsible (along with
the
preceding nerves) for the transmission of pain impulses from the soft palate
to the
brain.
[0028] Figure 2 illustrates the spray angles of the tip of the device (with
respect
to the horizontal plane) during administration of a nasal formulation.
DETAILED DESCRIPTION OF THE INVENTION
[0029] In order that the invention herein described may be fully understood,
the
following detailed description is set forth.
[0030] Unless defined otherwise, all technical and scientific terms used
herein
have the same meaning as those commonly understood by one of ordinary skill in
the art to which this invention belongs. Although methods and materials
similar or
equivalent to those described herein can be used in the practice or testing of
the
present invention, suitable methods and materials are described below. The
materials, methods and examples are illustrative only, and are not intended to
be
limiting. All publications, patents and other documents mentioned herein are
incorporated by reference in their entirety.
[0031] Throughout this specification, the word "comprise" or variations such
as
"comprises" or "comprising" will be understood to imply the inclusion of a
stated
integer or groups of integers but not the exclusion of any other integer or
group of
integers.
[0032] In order to further define the invention, the following terms and
definitions are provided herein.
Definitions
[0033] "Anesthetizing" as used herein refers to administering an anesthetic
compound (e.g., tetracaine or tetracaine HCI) for the purpose of preventing
sensation and/or reducing pain.
[0034] "Intranasal formulation" as used herein refers to a formulation that is
delivered to the nasal cavity and/or nasal sinuses.
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[0035] "Local anesthetic" as used herein refers to an anesthetic delivered
near the
nerve ending to be anesthetized which diffuses after introduction inside the
tissue.
A local anesthetic is capable of penetrating the tissue deep enough so as to
reach
the target nerves and nerve branches. A local anesthetic is different from a
"topical
anesthetic" in that a topical anesthetic only provides surface anesthesia to a
depth
of approximately 1-2 mm. A topical anesthetic does not penetrate deep enough
in
the tissue to reach nerve branches or teeth.
[0036] "Maxilla" as used herein refers to either of a pair of bones of the
human
skull fused to form the upper jaw. The maxilla is sometimes simply referred to
as
the upper jaw.
[0037] "Maxillary dental arch" or "maxillary arch" as used herein refers to
the
curved structure formed by the maxillary (upper) teeth in their natural
position.
[0038] "Mucosal tissue" or "mucous tissue" as used herein refers to a type of
epithelial tissue. Mucosal tissue refers to the layer of tissue which covers
the
surface of organs or lines a cavity. Non-limiting examples of mucosal tissue
include, tissue in the ear, throat, mouth, eye, nose, rectal area and/or the
urogenital
tract (such as the vagina).
[0039] "Oxymetazoline" as used herein refers to 3-(4,5-dihydro-1H-imidazol-2-
ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol and any salt thereof. Oxymetazoline
HC1 refers to the HC1 salt of 3-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2,4-
dimethyl-6-tert-butyl-phenol. Oxymetazoline is an al-adrenergic agonist and a
partial a2-adrenergic agonist.
[0040] "Pulpal anesthesia" as used herein refers to a level of anesthesia such
that
when a electric pulp testing (EPT) stimulation (i.e., a reading of 65 on the
pulp
tester) is administered to a tooth, the subject indicates no pain sensation in
the
tooth.
[0041] "Preceding nerves" as used herein refers to nerve endings and nerves
located upstream, usually present in a more central neural bundle, from a
particular
reference nerve.
[0042] "Subject" as used herein refers to an animal including a mammal (e.g.,
a
human).
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[0043] "Tetracaine" (sometimes referred to as "amethocaine") as used herein
refers to (2-(dimethylamino)ethyl 4-(butylamino)benzoate) and any salt
thereof.
Tetracaine HCI refers to the HCI salt of 2-(dimethylamino)ethyl 4-
(butylamino)benzoate.
Pharmaceutical Compositions
[0044] The present invention provides tetracaine based anesthetic
formulations.
These formulations are useful for anesthetizing the maxillary back molars,
including the distal half of the first molar, second and third molars. In one
aspect,
the present invention provides a pharmaceutical composition for anesthetizing
the
maxillary back molars by intranasal administration. In some embodiments, the
composition is for anesthetizing the maxillary second and third molars.
[0045] In some embodiments, the present invention provides intranasal
formulations of tetracaine. In some embodiments, the present invention
provides
intranasal formulations of tetracaine HCI. Such formulations are useful for
anesthetizing the maxillary back molars including the distal half of the first
molar,
second and third molars and pain fibers innervating the maxillary dental arch.
In
some embodiments, the formulation is for anesthetizing the maxillary second
and
third molars and pain fibers innervating the maxillary dental arch. Such
formulations are useful as local anesthetics.
[0046] Tetracaine is unique in that it is both stable and highly protein bound
compared to nearly all other local anesthetics. Because of its protein-bound
nature
and smaller molecular weight, tetracaine is better able to penetrate and
adhere to
the protein-covered membranes of nerve cells and is better able to penetrate
the
nerve so as to induce an anesthetic effect (especially when present in a
formulation
containing at least some of, e.g., vasoconstrictors, surfactants, emulsifiers,
solvents, pH modifiers and preservatives) when compared to other ester-based
anesthetics such as cocaine, procaine, chloroprocaine and benzocaine. In
addition,
other ester-based local anesthetics are very toxic in small amounts and have
also
been shown to be unstable. Amide-based local anesthetics such as lidocaine,
mepivacaine, bupivacaine, etidocaine, prilocaine, and ropivacaine, while
protein
bound, are not as effective as tetracaine (especially when tetracaine is part
of one
of the formulations of the present invention).
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[0047] As such, the present invention provides a pharmaceutical composition
suitable for administration of tetracaine or a pharmaceutically acceptable
salt
thereof. In certain embodiments, the pharmaceutical composition comprises a)
tetracaine, or a pharmaceutically acceptable salt thereof; b) a
vasoconstrictor; and
c) a pharmaceutically acceptable carrier. In other embodiments, the
pharmaceutical composition comprises a) tetracaine, or a pharmaceutically
acceptable salt thereof; b) a vasoconstrictor; c) a preservative; d) a
viscosity
enhancing agent; and e) a pharmaceutically acceptable carrier. In some
embodiments, the composition comprises about 2.0-5.0% (w/v) tetracaine. In
some embodiments, the composition comprises about 2.25-4.75% (w/v) tetracaine.
In other embodiments, the composition comprises about 2.5-4.0% (w/v)
tetracaine.
In yet other embodiments, the pharmaceutical composition comprises about 2.5-
3.5% (w/v) tetracaine. In a particular embodiment, the pharmaceutical
composition comprises about 3% (w/v) tetracaine. In some embodiments, the
pharmaceutical composition is for intranasal administration.
[0048] The present invention also provides a pharmaceutical composition
suitable for administration of tetracaine HCI. In certain embodiments, the
pharmaceutical composition comprises a) tetracaine HC1; b) a vasoconstrictor;
and
c) a pharmaceutically acceptable carrier. In other embodiments, the
pharmaceutical composition comprises a) tetracaine HCI; b) a vasoconstrictor;
c) a
preservative; d) a viscosity enhancing agent; and e) a pharmaceutically
acceptable
carrier. In some embodiments, the composition comprises about 2.0-5.0% (w/v)
tetracaine HCI. In some embodiments, the composition comprises about 2.25-
4.75% (w/v) tetracaine HCI. In other embodiments, the composition comprises
about 2.5-4.0% (w/v) tetracaine HCI. In yet other embodiments, the
pharmaceutical composition comprises about 2.5-3.5% (w/v) tetracaine HCI. In a
particular embodiment, the pharmaceutical composition comprises about 3% (w/v)
tetracaine HCI. In some embodiments, the pharmaceutical composition is for
intranasal administration.
[0049] Any vasoconstrictor may be used in the pharmaceutical composition of
this invention. The vasoconstrictors used in the pharmaceutical compositions
of
the invention has several purposes. First, the vasoconstrictor shrinks the
tissue
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(e.g., nasal tissue) thereby enhancing penetration of the anesthetic into the
tissue
(e.g., deeper into the nasal cavity). Second, once the vasoconstrictor has
been
absorbed into the desired area, it inhibits systemic migration of the
anesthetic,
thereby allowing the anesthetic to remain at a desired site. Third, the
vasoconstrictor reduces blood flow to the desired tissue, thereby increasing
the
duration of the anesthetic's effectiveness (typically by activating G-protein
coupled
receptors which render metallic ionophores in the nerve membrane more
sensitive
to the tetracaine base). Typical vasoconstrictors useful in the pharmaceutical
compositions of this invention include but are not limited to indirect ai-
adrenergic
agonists such as phenylephrine; calcium channel blockers; meperidine;
imidazole
drugs such as oxymetazoline and xylometazoline; a2-adrenergic agonists such as
guanfacine; imidazoline (II) ligands; direct a2-adrenergic agonists such as
clonidine; substance P blockers/reducers such as capsaicin; I-menthol; icilin;
and
glutamate receptor inhibitors; or pharmaceutically acceptable salts thereof.
The
vasoconstrictor can also be a compound that activates a G-protein coupled
receptor. In some embodiments, the vasoconstrictor includes but is not limited
to
oxymetazoline, xylometazoline, guanfacine, clonidine, phenylephrine,
meperidine,
capsaicin; I-menthol; icilin and pharmaceutically acceptable salts thereof. In
some
embodiments, the vasoconstrictor is oxymetazoline, or a pharmaceutically
acceptable salt thereof. In other embodiments, the oxymetazoline is an
oxymetazoline HC1 salt.
[0050] The concentration of vasoconstrictor used in the pharmaceutical
composition of the instant invention will depend on the specific
vasoconstrictor
and the desired vasoconstricting effect. Typical ranges of concentrations
include
but are not limited to about 0.005-5% (w/v). In some embodiments, the
composition comprises about 0.005-0.01% (w/v) (e.g., oxymetazoline HC1 salt).
In some embodiments, the composition comprises about 0.01-1.0% (w/v) (e.g.,
oxymetazoline HC1 salt). In yet other embodiments, the composition comprises
about 0.05% (w/v) (e.g., oxymetazoline FICI salt).
[0051] In addition to its vasoconstricting activity, oxymetazoline has been
shown
to have a degree of anesthetic affect. Oxymetazo line affects G-protein
coupled
receptors and, in turn, K+, Na, and Ca2+ channels present in nerve cells. In
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particular, oxymetazoline enhances K+, Nat, and Ca2+ permeability such that
the
nerve is no longer polarized and, thus, is unable to fire and transmit pain
impulses.
[0052] In some embodiments, the pharmaceutical composition of this invention
further comprises a preservative. Examples of preservatives include, but are
not
limited to sugar alcohols (e.g., sorbitol and mannitol), ethanol, benzyl
alcohol,
isopropanol, cresol, chlorocresol, phenol and benzalkonium chloride (BAK). In
some embodiments, the preservative is benzyl alcohol. Benzyl alcohol is
particularly desirable because it exhibits an anesthetic effect and works to
enhance
the effect of tetracaine in a synergistic manner.
[0053] The concentration of preservative used in the pharmaceutical
composition
of the instant invention will depend on the specific preservative. Typical
ranges of
concentrations of preservatives are about 0.1-5 % (w/v). In some embodiments,
the composition comprises about 0.5-2.0% (w/v). In other embodiments, the
composition comprises about 0.9% (w/v) (e.g., benzyl alcohol).
[0054] The anesthetic, vasoconstrictor and other agents used in the
compositions
of the present invention may be dispersed in an appropriate carrier in order
to
control the dosage, absorption rate and other desired properties.
Pharmaceutically
acceptable carriers useful in the present invention include but are not
limited to
aqueous carriers, gel carriers, emulsifiers, surfactants, time release
vehicles,
nanoparticles, microspheres, intra- and para-cellular transport chemicals,
polymers,
and chitin. Examples of aqueous carriers include, but are not limited to,
water,
buffers (e.g., phosphate buffer, citrate buffer), sugar alcohols, alcohols
such as
ethanol, or any other solvent that is biologically compatible with the target
tissue.
[0055] Saline is not an appropriate carrier for use with the compositions of
the
present invention. Specifically, it has been discovered that the compositions
of the
present invention are unstable in saline.
[0056] The pH of the pharmaceutical composition of the present invention is
typically adjusted to be compatible with the pH of the tissue to which it is
being
administered (e.g., the nasal cavity). Typically, the composition has a pH of
about
4.0-6.5. In some embodiments, the composition has a pH of about 5.5-6.5. In
further embodiments, the pharmaceutical composition has a pH of about 6.0 to
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about 6.5. The skilled artisan will appreciate that higher or lower pHs than
those
recited may be required and would readily know how to adjust the pH
accordingly.
[0057] In some embodiments, the pharmaceutical composition of this invention
further comprises a viscosity enhancing agent. Examples of viscosity enhancing
agents include, but are not limited to methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose and smart hydrogel. In some embodiments, the
viscosity enhancing agent is hydroxyethylcellulose.
[0058] Viscosity enhancing agents aid in controlling the mobility of the
formulation before, during, and after application of the formulation to a
target
tissue. For example, viscosity enhancing agents aid in controlling the amount
of
formulation that either drips out of the nostrils or into the throat of the
subject by
reducing the mobility of the applied formulation. Viscosity enhancing agents
also
increase the amount of time the formulation is in contact with the vasculature
(e.g.,
nasal vasculature) which helps to increase the uptake efficiency of the
formulation
to the vasculature. In addition, viscosity enhancing agents further dilute
moieties
present in the nasal passage that degrade esters (e.g., esterase) and can be
mildly
cilio-inhibitory.
[0059] The concentration of viscosity enhancing agent used in the
pharmaceutical composition of the instant invention will depend on the
specific
viscosity enhancing agent. Typical ranges of viscosity enhancing agents,
include
0.01 to 5% (w/v). In some embodiments, the pharmaceutical composition
comprises about 0.01-1.0% (w/v). In other embodiments, the composition
comprises about 0.05% (w/v) (e.g., hydroxyethylcellulose). The inventors have
observed that compositions comprising high amounts of viscosity enhancing
agents
(e.g., hydroxyethylcellulose) result in clogging of the spray apparatus (e.g.,
the BD
AccusprayTM device).
[0060] In one embodiment, the pharmaceutical composition of the present
invention comprises the following components: tetracaine HCI, oxymetazoline
HCI, anhydrous citric acid (for pH control), sodium hydroxide (for pH
adjustment),
benzyl alcohol, hydrochloric acid (for pH control), hydroxyethylcellulose, and
purified water. In a particular embodiment, the pharmaceutical composition is
for
intranasal administration.
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[0061] In another embodiment, the pharmaceutical composition of the present
invention comprises the following components: tetracaine HCI, oxymetazoline
HCI, anhydrous citric acid (for pH control), anhydrous sodium citrate (for pH
control), sodium hydroxide (for pH adjustment), benzyl alcohol, hydrochloric
acid
(for pH control), hydroxyethylcellulose, and purified water.
[0062] In another embodiment, the pharmaceutical composition of the present
invention comprises the following components: tetracaine HC1, oxymetazoline
HCI, anhydrous citric acid (for pH control), sodium citrate dihydrate (for pH
control), sodium hydroxide (for pH adjustment), benzyl alcohol, hydrochloric
acid
(for pH control), hydroxyethylcellulose, and purified water.
[0063] In a particular embodiment, the pharmaceutical composition of the
present invention is the Table 1 formulation. In another embodiment, the Table
1
formulation is for intranasal administration.
[0064] In one embodiment, the Table I formulation has a pH of between about
4.0-6.5. In another embodiment the Table 1 formulation has a pH of between
about 5.5-6.5. In another embodiment the Table 1 formulation has a pH of about
6.0 to about 6.5.
[0065] The pharmaceutical compositions of the present invention may be
administered in several forms. Examples of suitable formulations include, but
are
not limited to, liquids (e.g., solutions), sprays, suspensions, gels, foams,
oils,
powders, or emulsions.
[0066] One of skill in the art will appreciate that the type of formulation
used
will depend on, for example, the amount of active ingredient to be
administered
and the target tissue.
[0067] Suitable gel formulations may comprise, for example, modified
celluloses
(e.g., hydroxypropyl cellulose and hydroxyethyl cellulose), carbopol
homopolymers and copolymers, solvents such as diglycol monoethyl ether,
alkylene glycols (e.g., propylene glycol), dimethyl isosorbide, alcohols
(e.g.,
isopropyl alcohol and ethanol), isopropyl myristate, ethyl acetate, C12-Cis
alkyl
benzoates, mineral oil, squalane, cyclomethicone, capric/caprylic
triglycerides, or
combinations thereof.
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[0068] Suitable foam compositions may comprise, for example, an emulsion and
a gaseous propellant. Examples of gaseous propellants include, but are not
limited
to, hydrofluoroalkanes (HFAs) such as 1,1,1,2-tetrafluoroethane (HFA 134a) and
1,1,1,2,3,3,3-heptafluoropropane (HFA 227).
[0069] Suitable oil formulations may comprise, for example, natural and
synthetic oils, fats, fatty acids, lecithins, triglycerides, or combinations
thereof.
[0070] Suitable ointment formulations may comprise, for example, hydrocarbon
bases (e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil),
absorption bases (e.g., hydrophilic petrolatum, anhydrous lanolin, lanolin,
and cold
cream), water-removable bases (e.g., hydrophilic ointment), water-soluble
bases
(e.g., polyethylene glycol ointments), propylene glycol, polyoxyethylene,
polyoxypropylene, emulsifying wax, or combinations thereof.
[0071] In other embodiments, the pharmaceutical composition optionally
comprises a pharmaceutically acceptable excipient. Examples of
pharmaceutically
acceptable excipients include, but are not limited to, preservatives,
surfactants,
stabilizing agents, emulsifiers, antibacterial agents, buffering agents and
viscosity
modifying agents. Specific examples of such excipients are discussed above.
[0072] Examples of emulsifiers include, but are not limited to, acacia,
anionic
emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl
alcohol,
cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin
monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose,
lanolin,
hydrous, lanolin alcohols, lecithin, medium-chain triglycerides,
methylcellulose,
mineral oil and lanolin alcohols, monobasic sodium phosphate,
monoethanolamine,
nonionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene
alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan
fatty
acid esters, polyoxyethylene stearates, propylene glycol alginate, self-
emulsifying
glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate,
sorbitan
esters, stearic acid, sunflower oil, tragacanth, triethanolamine and xanthan
gum.
Methods of Anesthetizing the Maxillary Back Molars
[0073] In one aspect, the invention provides a method for anesthetizing the
maxillary back molars, including the distal half of the first molar, second
and third
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molars (and pain fibers external to the dental arch) in a subject comprising
selectively delivering near or in the nasal cavity of the subject a
pharmaceutical
composition of the invention, wherein at least a portion of the pharmaceutical
composition is absorbed by nasal tissue located at the rear of the nasal
cavity in the
vicinity of the superior dental plexus, the infra-orbital branch of the
maxillary
nerve, the posterior superior alveolar nerve, the sphenopalatine ganglion, the
nerves under the Schneiderian membrane, and/or the pterygopalatine fossa
(sphenopalatine fossa), thereby anesthetizing the maxillary back molars
including
the distal half of the first molar, second and third molars (and pain fibers
outside
but around the maxillary arch of the subject) of the subject. In other
embodiments,
the invention provides a method for anesthetizing the maxillary second and
third
molars (and pain fibers external to the dental arch) in a subject comprising
selectively delivering near or in the nasal cavity of the subject a
pharmaceutical
composition of the invention, wherein at least a portion of the pharmaceutical
composition is absorbed by nasal tissue located at the rear of the nasal
cavity in the
vicinity of the superior dental plexus, the infra-orbital branch of the
maxillary
nerve, the posterior superior alveolar nerve, the sphenopalatine ganglion, the
nerves under the Schneiderian membrane, and/or the pterygopalatine fossa
(sphenopalatine fossa), thereby anesthetizing the maxillary second and third
molars
(and pain fibers outside but around the maxillary arch of the subject) of the
subject.
In some embodiments, the pharmaceutical composition is delivered into the
nasal
sinuses and/or the rear of the nasal cavity of the subject. In some
embodiments,
the maxillary back molars are anesthetized without producing facial numbness
of
the eye, surface of the nose, cheeks or lips. In some embodiments, the tissues
around the maxillary back molars (e.g., mucosal tissue such as gums) are also
anesthetized. In some embodiments, the maxillary second and third molars are
anesthetized without producing facial numbness of the eye, surface of the
nose,
cheeks or lips. In some embodiments, the tissues around the maxillary second
and
third molars (e.g., mucosal tissue such as gums) are also anesthetized. In
some
embodiments, the pharmaceutical composition is delivered by nebulization or
spraying. In some embodiments, the pharmaceutical composition is delivered to
the nasal sinuses such as the maxillary sinus. In other embodiments, the
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pharmaceutical composition is delivered to the superior dental plexus, the
infra-
orbital branch of the maxillary nerve, the posterior superior alveolar nerve,
the
sphenopalatine (pterygopalatine) ganglion, the nerves under the Schneiderian
membrane, and/or the pterygopalatine fossa (sphenopalatine fossa). In other
embodiments, the delivered spray is a stream or a plume. In some embodiments,
the method is for anesthetizing the maxillary second and third molars.
[0074] In order to anesthetize the maxillary back molars, the pharmaceutical
composition is administered to the tissue located at the extreme rear upper
end of
the nasal cavity such that the composition is absorbed in the region of the
superior
dental plexus, the infra-orbital branch of the maxillary nerve, the posterior
superior
alveolar nerve, the sphenopalatine (pterygopalatine) ganglion, and/or the
nerves
under the Schneiderian membrane.
[0075] Any delivery device may be used in the methods of the present
invention.
Examples of delivery devices suitable for intranasal administration include,
but are
not limited to squeeze bottles, syringes, pneumatically pressurized devices,
pump
sprayers, positive pressure nebulizers and the like. In some embodiments, the
device used is pre-filled with a pharmaceutical composition of the present
invention. In another embodiment, the device used is a BD AccusprayTM device.
[0076] In some embodiments, the method comprises spraying the pharmaceutical
composition 1-5 times into each of the nostrils of the subject. In other
embodiments, the method comprises spraying the pharmaceutical composition 3
times into each of the nostrils of the subject.
[0077] In some embodiments, the method comprises spraying the pharmaceutical
composition 1-5 times into one of the nostrils of the subject. In other
embodiments, the method comprises spraying the pharmaceutical composition 3
times into one of the nostrils of the subject.
[0078] Without being bound by any particular theory, it is believed that the
each
spraying may play a unique role in the onset of the anesthetic effect. For
example,
in embodiments wherein the pharmaceutical composition is delivered in 3
sprays,
it is believed that the first spray begins to neutralize nasal enzymatic
pathways
(e.g., esterases, cytochrome P450, aldehyde dehydrogenase), which may
breakdown the delivered pharmaceutical composition. It is also believed that
the
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first spray begins to paralyze the nasal cilia which may otherwise clear the
composition to, for example, the pharynx. It is further believed that the
composition delivered in the second and third sprays bring on the anesthetic
effect.
[0079] In some embodiments, each of the sprays are administered within about
1-10 minutes of each other. For example, spray #1 may be administered,
followed
by an interval of about 1-10 minutes, after which spray #2 is administered,
followed by an interval of about 1-10 minutes, after which spray #3 is
administered, etc. In some embodiments, the interval between sprays is about 1-
6
minutes. In some embodiments, the interval between sprays is about 2-6
minutes.
In other embodiments, the interval between sprays is about 3-5 minutes. In yet
other embodiments, the interval between sprays is about 4 minutes.
[0080] The pharmaceutical compositions of the present invention are delivered
to
the superior dental plexus, the infra-orbital branch of the maxillary nerve,
the
posterior superior alveolar nerve, the sphenopalatine (pterygopalatine)
ganglion,
the nerves under the Schneiderian membrane, and/or the pterygopalatine fossa
(sphenopalatine fossa). Further, the pharmaceutical compositions of the
present
invention anesthetize at least a portion of the superior dental plexus, the
infra-
orbital branch of the maxillary nerve, the posterior superior alveolar nerve,
the
sphenopalatine (pterygopalatine) ganglion, and/or the nerves under the
Schneiderian membrane In some embodiments, the pharmaceutical composition is
delivered to the posterior superior alveolar nerve.
[0081] In embodiments where the method comprises spraying the pharmaceutical
composition into the subject's nose, it has been found that the angle of
spraying
aids in targeting the formulation to the relevant portions of the nasal cavity
described above. For example, and without being bound by the following
techniques, it is believed that to target the maxillary second and third
molars (i.e.,
teeth 1, 2, 15, and 16), the spray device is angled about 0 to 10 degrees away
from
midsagittal plane. In other embodiments, the spray device is angled about 5
degrees away from midsagittal plane for the maxillary second and third molars.
In
some embodiments, the method is for anesthetizing the maxillary back molars,
including the distal half of the first molar, second and third molars.
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[0082] Tooth targeting may be further refined by varying the depth at which
the
spray device is placed within the nostril. For example, when spraying, the
spray
device can be placed about 7-9 mm into the nostril to target the maxillary
back
molars (e.g., the distal half of the first molar, second and third molars)
(i.e., at the
opening of the internal nasal valve). In some embodiments, the method is for
anesthetizing the maxillary second and third molars.
[0083] The patient's position during administration of the formulation can
also
effect the extent the maxillary back molars, including the distal half of the
first
molar, second and third molars are anesthetized. For example, the maxillary
back
molars are more efficiently anesthetized when the formulation is administered
to a
patient who is in a semi-reclining or reclining position. Thus, in some
embodiments, the pharmaceutical composition is intranasally administered to a
patient in a semi-reclining position. In other embodiments, the pharmaceutical
composition is intranasally administered to a patient in a reclining position.
In
some embodiments, a single spray or multiple sprays can be given in one or
both
nostrils such that the angle or sweeping motion covers the nasal cavity beyond
the
internal nasal valve. In some embodiments, the method is for anesthetizing the
maxillary second and third molars.
[0084] In some embodiments, a known (e.g., metered) amount of tetracaine is
delivered near or in the nasal cavity of the subject. In other embodiments,
the
known (e.g., metered) amount of tetracaine is delivered into the nasal sinuses
and/or rear of the nasal cavity of the subject. Typically, the amount of
tetracaine
delivered to the nasal sinuses and/or rear of the nasal cavity of the subject
is about
12-50 mg of tetracaine. In some embodiments, about 15-24 mg of tetracaine is
delivered into the nasal sinuses and/or rear of the nasal cavity of the
subject. In
some embodiments, about 15-20 mg of tetracaine is delivered into the nasal
sinuses
and/or rear of the nasal cavity of the subject. In some embodiments, about 18
mg
of tetracaine is delivered in the nasal sinuses and/or rear of the nasal
cavity of the
subject. In some embodiments, the composition comprises about 2.0-5.0% (w/v)
tetracaine. In some embodiments, the composition comprises about 2.25-4.75%
(w/v) tetracaine. In other embodiments, the composition comprises about 2.5-
4.0% (w/v) tetracaine. In yet other embodiments, a composition comprising
about
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2.5-3.5% (w/v) tetracaine is used. In a particular embodiment, the composition
comprises about 3% (w/v) tetracaine. The inventors have observed that
compositions comprising 2% tetracaine do not result in pulpal anesthesia,
possibly
due to insufficient amounts of tetracaine. The inventors also observed that
compositions comprising 4% tetracaine do not result in pulpal anesthesia,
possibly
due to the onset of tachyphylaxis.
[0085] In some embodiments, a known (e.g., metered) amount of tetracaine HCI
is delivered near or in the nasal cavity of the subject. In other embodiments,
the
known (e.g., metered) amount of tetracaine HCI is delivered into the nasal
sinuses
and/or rear of the nasal cavity of the subject. Typically, the amount of
tetracaine
delivered to the nasal sinuses and/or rear of the nasal cavity of the subject
is about
12-50 mg of tetracaine HCI. In some embodiments, about 15-24 mg of tetracaine
HCI is delivered into the nasal sinuses and/or rear of the nasal cavity of the
subject.
In some embodiments, about 15-20 mg of tetracaine HCI is delivered into the
nasal
sinuses and/or rear of the nasal cavity of the subject. In some embodiments,
about
18 mg of tetracaine HCI is delivered in the nasal sinuses and/or rear of the
nasal
cavity of the subject. In some embodiments, the composition comprises about
2.0-
5.0% (w/v) tetracaine HCI. In some embodiments, the composition comprises
about 2.25-4.75% (w/v) tetracaine HCI. In other embodiments, the composition
comprises about 2.5-4.0% (w/v) tetracaine HCI. In yet other embodiments, a
composition comprising about 2.5-3.5% (w/v) tetracaine HCI is used. In a
particular embodiment, the composition comprises about 3% (w/v) tetracaine
HCI.
The inventors have observed that compositions comprising 2% tetracaine (e.g.,
2%
tetracaine HCI) do not result in pulpal anesthesia, possibly due to
insufficient
amounts of tetracaine HCI. The inventors also observed that compositions
comprising 4% or more tetracaine (e.g., 4% tetracaine HCI) were not as
effective
in inducing pulpal anesthesia.
[0086] In some embodiments, the particle size of the pharmaceutical
composition
delivered to the nasal sinuses and/or rear of the nasal cavity is about 5-50
microns.
In other embodiments, the particle size of the pharmaceutical composition is
about
10-20 microns. In some embodiments, the pharmaceutical composition is
delivered in a manner such that at least 50% of the particles are at least
about 10
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microns or larger. In other embodiments, the pharmaceutical composition is
delivered in a manner such that at least 65% of the particles are at least
about 10
microns or larger. In other embodiments, the pharmaceutical composition is
delivered in a manner such that at least 85% of the particles are at least
about 10
microns or larger. In yet other embodiments, the pharmaceutical composition is
delivered in a manner such that at least 90% of the particles are at least
about 10
microns or larger. In further embodiments, the pharmaceutical composition is
delivered in a manner such that at least 95% of the particles are at least
about 10
microns or larger.
[0087] These and other embodiments of the invention may be further illustrated
in the following non-limiting Examples.
EXAMPLES
Example 1: Dose-Ranging Study of Tetracaine Hydrochloride with
Oxymetazoline Hydrochloride for Anesthetizing Maxillary Second and Third
Molars
[0088] To identify an effective and safe dosage of tetracaine hydrochloride
with
oxymetazoline HCI when administered by nasal spray for anesthesia of the
maxillary second and third molars, two formulations are administered to human
patients using a BD AccusprayTM device ¨ one with 3% tetracaine and 0.05%
oxymetazoline; and another with 4% tetracaine and 0.05% oxymetazoline.
[0089] The formulation is administered at a spray device angle of
approximately
zero degrees from the horizontal plane and zero to 10 degrees from the
midsagittal
plane with the tip placed 7-9 mm inside the nostril (i.e., past the internal
nasal
valve) with the subject looking straight ahead. The efficacy of the
formulation is
measured by monitoring pain levels via electric pulp testing (EPT).
[0090] Three dosing regimes consisting of varying amounts of
tetracaine HCI:oxymetazoline are evaluated: a) 12:0.2; b) 16:0.2; and c)
18:0.3 mg
of tetracaine HCI:oxymetazoline HCI. The second and third molars are then
tested
for pulpal anesthesia (defined as having at least one test with no sensation
in the
tooth at maximum EPT stimulation, i.e., a reading of 80 on the pulp tester).
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Further, subjects are tested for profound anesthesia (defined as having pulpal
anesthesia beginning within 30 minutes after drug administration and
continuing
for at least 20 minutes in the first hour of testing on at least one of teeth
tested).
Example 2: Evaluation of Table 1 Formulation for Anesthetizing Maxillary
Second and Third Molars in Healthy Subjects
[0091] The Table 1 formulation is evaluated to determine if it: a) provides
anesthesia of the maxillary second and third molars sufficient for the
performance
of dental procedures, and provides anesthesia of soft tissue; and b) is safe
and
tolerable compared to a sham nasal spray of isotonic saline in the BD
AccusprayTM
device, an active control injection of 2% lidocaine hydrochloride dental local
anesthetic infiltration injection, and a sham injection.
Test Subjects
[0092] Human subjects (some receiving the Table 1 formulation and some
receiving Lidocaine) are tested. All subjects require, for example, an
operative
restorative procedure on a single maxillary second or third molar with
treatment
time that is not expected to exceed 60 minutes.
Procedures
[0093] A schedule of the procedures is presented in Table 3.
Table 3: Schedule of Procedures
0 min Administer first dose of nasal spray and perform
injection (or
sham injection), followed by sips of water
4 min Administer second dose of nasal spray, followed by sips
of water
8 min Administer third dose of nasal spray, followed by sips of
water
15 min Begin dental procedure
20 min* Soft Tissue Assessment, VAS
min Soft Tissue Assessment
min Soft Tissue Assessment
min Soft Tissue Assessment
min** Global VAS, Soft Tissue Assessment
1 hr 20 min Soft Tissue Assessment
1 hr 40 min Soft Tissue Assessment
2 hr Soft Tissue Assessment
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*If subject is not sufficiently anesthetized to proceed with the dental
procedure at 15 minutes, start
at 20 minutes, immediately after Vital Signs and VAS
**VAS will be performed at the end of the dental procedure, regardless of the
timepoint.
Abbreviations: VAS = Visual Analog Scale
Overview of Procedure
[0094] Subjects are randomly assigned a treatment group and treatment order.
The order of active drug administration (intranasal versus injection) is also
random. Assessment of soft tissue anesthesia is made prior to dosing, and at
20,
30, 40, 60, 80, 100, and 120 minutes after dosing. At 0 min, either a) a
single
intraoral injection of lidocaine with epinephrine and sham nasal spray of
isotonic
saline is given; or b) a sham injection (depending on randomization group) and
administration of a spray of the Table 1 formulation is administered.
Additional
doses of nasal spray are administered at 4 and 8 minutes. Subjects sip
approximately 2 oz of water following each active or placebo nasal spray dose.
The Heft-Parker visual analog scale (VAS) is administered at 15 and 20 minutes
after start of dosing. Dental treatment commences 4 minutes after the last
dose is
given. If patients report pain, the dental treatment does not commence until
the 20
minute mark and an additional VAS test is given. Vital signs (heart rate,
blood
pressures, pulse oximetry) are taken before dosing, 15 minutes after the start
of
dosing, and at 20, 30, 40, 50, 60, and 120 minutes after the start of dosing.
Global
efficacy assessments are made at the end of treatment.
Test Product(s), Dose, and Mode of Administration
[0095] The Table 1 formulation is delivered in a BD Accuspraye mono-dose
nasal spray device with backstop (BD Medical-Pharmaceutical Systems, Franklin
Lakes, New Jersey). Dose delivery is controlled by the solution concentration
and
volume contained in each syringe. All units are filled to deliver 0.2 mL. A
total of
three sprays of the Table 1 formulation are administered, with four minutes
between each nasal spray dose. The total dosing period spans 8 minutes. The
total
dosage of the Table 1 formulation is 18 mg tetracaine HCI and 0.3 mg
oxymetazo line HCI.
[0096] The sham nasal spray consists of isotonic saline solution.
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[0097] The active control injection consists of 2% lidocaine HCI and
epinephrine
(1:100,000) USP (LolliCaine single-use applicators, Centrix). The injection is
performed with a 30-gauge short needle inserted submucosally approximating the
apex of the tooth to be treated. The dosage of the 2% lidocaine hydrochloride
with
1:100,000 epinephrine injection consists of one cartridge (1.8 mL) delivered
over
60 seconds for the treatment of a second or third molar.
[0098] The sham injection consists of a dental syringe and lidocaine with
epinephrine cartridge but with the cap left on a 30-gauge short needle tip.
The
needle cap is held against the mucosa in the proper position for the injection
for 60
seconds for the second or third molars. No solution is injected.
[0099] A small amount of 20% benzocaine gel is used on all subjects to provide
topical anesthesia 1 minute before active or sham needle insertions.
[0100] The rescue therapy consists of 4% articaine hydrochloride with
1:100,000
epinephrine injection (Septocaine, Septodont).
[0101] The Dosing Algorithm consists of:
= Administration of topical benzocaine gel 1 min before dosing with sham or
active injection
= Administration dose of injection or initial dose of nasal spray (T=0 min)
= If initial dose is nasal spray, at 4 min, administration of a second dose
of
nasal spray
= If initial dose is nasal spray, at 8 min, administration of a third dose
of nasal
spray
= At 15 min, proceeding with dental treatment
[0102] Subjects sip approximately 2 oz of water one minute after each dose of
nasal spray (i.e., at approximately 2 and 5 min, and at 10 min). When subjects
report pain at the onset of dental treatment, the dentist stops treatment and
waits
five minutes (to a total of 20 minutes post start of dosing). Subjects who
continue
to report pain at resumption of dental treatment are considered "treatment
failures"
and are given rescue therapy.
Administration of Treatment
[0103] For each spray, the subject is in a semi-reclining or reclining
position.
The tip of the spray device is placed at the opening of the internal nasal
valve
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(approximately 7-9 mm inside the nose) at an angle of 0 degrees from the
horizontal plane and zero to 10 degrees from the midsagittal plane; the
subject
looks straight ahead. During each spray, the subject is instructed to hold
his/her
breath. After each spray the subject is asked to gently sniff and to turn
their head
to the side that was sprayed (i.e., to turn their head to same side as the
nostril in
which the spray was administered).
Assessment of Efficacy
[0104] In order to assess soft tissue anesthesia, a dental professional uses a
pressure sensitive mechanical probe (e.g., Rotadente) and tests the following
areas
for soft tissue anesthesia: posterior to the first molar at the deepest point
in the
buccal vestibule; and near the greater palatine foramen. For each site tested,
the
subject is asked if they feel pain. Efficacy of the formulation is determined
by the
ability to accomplish the dental procedure without the need for rescue drug.
Example 3: Evaluation of Table 1 Formulation on Maxillary Second Molar by
EPT
[0105] The Table 1 formulation was evaluated by monitoring pain levels via
EPT. Twenty-five subjects were treated and tested for numbness of the
maxillary
first or second molar. Of the twenty-five subjects, three were tested on the
second
molar. All three subjects demonstrated numbness by indicating no pain
sensation
in the tooth at an EPT reading of 65 or higher. The EPT results of the three
subjects tested on the maxillary second molar are shown below in Table 4.
Table 4: Second Molar EPT
Minutes post- Patient 15 Patient 17 Patient 30
treatment
5 min prior 56 38 42
3 min 59 34 51
7 min 67 47 48
11 min 54 48 80
16 min 54 58 80
21 min 80 _ 80 29
26 min 80 52 41
31 min 73 54 80
41 min 57 55 40
51 min 66 47 37
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61 min 60 52 . 48
76 min 34 45 . 30
91 min 48 35 =48
121 min 53 43 53
151 min 52 39 , 40
181 min 61 43 80
,
