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 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 longstanding 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. [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 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).

[0011] 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 HC1. 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) tetracaine HC1. In yet other embodiments, the composition comprises about 2.5- 3.5% (w/v) tetracaine HC1. In other embodiments, the composition comprises about 3% (w/v) tetracaine HC1. 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;

a ₂ -adrenergic agonists such as guanfacine; imidazoline (I i) ligands; direct ά ₂ - 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 HC1 salt.

[0015] In some embodiments, the pharmaceutical composition comprises about 0.01- 1.0% (w/v) oxymetazoline HC1. In other embodiments, the pharmaceutical composition comprises about 0.05- 1 .0% (w/v) oxymetazoline HC1. In other embodiments, the pharmaceutical composition comprises about 0.05% (w/v) oxymetazoline HC1.

[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, 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 HCl, oxymetazoline HCl, and benzyl alcohol. In another embodiment, the pharmaceutical composition comprises tetracaine HCl, oxymetazoline HCl, 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 HCl, oxymetazoline HCl, 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 HCl, oxymetazoline HCl, 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 invention comprises the components, and respective amounts, listed in Table 1 below (referred to herein as the "Table 1 formulation").

Table 1

[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 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.

[0022] 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 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 HCI near or in the nasal cavity of the subject. In some embodiments, the method comprises delivering about 12-50 mg of tetracaine HCI 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 HCI 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 HCI 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 HCI 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 (μηι). 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 pharmaceutical composition of the present invention. In some embodiments, the spray device is capable of delivering the intranasal 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

[0027] 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 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 HC1) 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. [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-lH-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- lH-imidazol-2-ylmethyl)-2,4- dimethyl-6-tert-butyl-phenol. Oxymetazoline is an ai-adrenergic agonist and a partial <x ₂ -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). [0043] "Tetracaine" (sometimes referred to as "amethocaine") as used herein refers to (2-(dimethylamino)ethyl 4-(butylamino)benzoate) and any salt thereof. Tetracaine HC1 refers to the HC1 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 HC1. 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). [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 HCl. In certain embodiments, the pharmaceutical composition comprises a) tetracaine HCl; b) a vasoconstrictor; and c) a pharmaceutically acceptable carrier. In other embodiments, the

pharmaceutical composition comprises a) tetracaine HCl; 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 HCl. In some embodiments, the composition comprises about 2.25- 4.75% (w/v) tetracaine HCl. In other embodiments, the composition comprises about 2.5-4.0% (w/v) tetracaine HCl. In yet other embodiments, the

pharmaceutical composition comprises about 2.5-3.5% (w/v) tetracaine HCl. In a particular embodiment, the pharmaceutical composition comprises about 3% (w/v) tetracaine HCl. 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 (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; ₂ -adrenergic agonists such as guanfacine; imidazoline (li) ligands; direct a ₂ -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 HC1 salt).

[0051] In addition to its vasoconstricting activity, oxymetazoline has been shown to have a degree of anesthetic affect. Oxymetazoline affects G-protein coupled receptors and, in turn, K ⁺ , Na ⁺ , and Ca ²⁺ channels present in nerve cells. In particular, oxymetazoline enhances ⁺ , Na ⁺ , and Ca ²⁺ 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 (BA ). 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 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 Accuspray™ device).

[0060] In one embodiment, the pharmaceutical composition of the present invention comprises the following components: tetracaine HCl, oxymetazoline HCl, 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. [0061] In another embodiment, the pharmaceutical composition of the present invention comprises the following components: tetracaine HC1, oxymetazoline HC1, 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 HC1, 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 1 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-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric/caprylic triglycerides, or combinations thereof. [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 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 pharmaceutical composition is delivered to the superior dental plexus, the infraorbital 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 Accuspray™ 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 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 infraorbital 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. [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 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 HCl is delivered near or in the nasal cavity of the subject. In other embodiments, the known (e.g., metered) amount of tetracaine HCl 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 HCl. In some embodiments, about 15-24 mg of tetracaine HCl 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 HCl is delivered into the nasal sinuses and/or rear of the nasal cavity of the subject. In some embodiments, about 18 mg of tetracaine HCl 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 HCl. In some embodiments, the composition comprises about 2.25-4.75% (w/v) tetracaine HCl. In other embodiments, the composition comprises about 2.5-4.0% (w/v) tetracaine HCl. In yet other embodiments, a composition comprising about 2.5-3.5% (w/v) tetracaine HCl is used. In a particular embodiment, the composition comprises about 3% (w/v) tetracaine HCl. The inventors have observed that compositions comprising 2% tetracaine (e.g., 2% tetracaine HCl) do not result in pulpal anesthesia, possibly due to insufficient amounts of tetracaine HCl. The inventors also observed that compositions comprising 4% or more tetracaine (e.g., 4% tetracaine HCl) 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 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 HCl when administered by nasal spray for anesthesia of the maxillary second and third molars, two formulations are administered to human patients using a BD Accuspray™ 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 HCl:oxymetazoline are evaluated: a) 12:0.2; b) 16:0.2; and c) 18:0.3 mg of tetracaine HCl:oxymetazoline HCl. 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). 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 Accuspray™ 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 in jection), 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

30 min Soft Tissue Assessment

40 min Soft Tissue Assessment

50 min Soft Tissue Assessment

60 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 *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, 1 5 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 Accuspray® 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 HC1 and 0.3 mg

oxymetazoline HC1.

[0096] The sham nasal spray consists of isotonic saline solution. [0097] The active control injection consists of 2% lidocaine HC1 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 (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., Rotadent®) 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

1 1 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 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