Therapeutic Compositions of Intranasal Lidocaine

Abstract

A method for treating pain using a nasal spray formulation and a locally acting sodium channel blocker is disclosed, wherein the nasal spray formulation comprises about 5% to about 30% w / v of a locally active sodium channel blocker, about 0.25% to about 5% w / v of a buffering agent, and about 5 to about 99% w / v of a pharmaceutically acceptable carrier for nasal administration. The nasal spray formulation is preferably contained in a mechanical multi-dose pump that sprays a unit dose of the nasal spray formulation with a wide plume and small droplet size, and the unit dose is administered by activating the mechanical multi-dose spray pump device and spraying a quantity of the nasal spray formulation into each nostril of a human subject. Preferably, the nasal spray formulation does not contain a preservative.

Description

[Technical field]

[0001] The present invention discloses a (preferably) preservative-free intranasal composition in a multi-dose or bi-dose or unit dose spray container for treating pain associated with trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache. [Background technology]

[0002] Preservative-free nasal preparations reveal some interesting aspects. Nasal preparations intended for long-term use are usually preserved. However, it is now recognized that preservatives have a negative effect on the ciliated tissue of the nasal cavity. The ciliary epithelium plays a crucial role in the function of the nose. The movement of the cilia serves to transport inhaled particles trapped in the nasal mucosa. The debris is directed towards the throat and then removed by swallowing. This clearing function prevents foreign bodies from reaching the lungs. The effect of preservatives on the cilia beating frequency can be described as ciliary inhibition. In case of nasal infections such as perennial rhinitis, the mucus of the nasal cavity is highly contaminated, so it is important to clear the infected mucus as soon as possible. To treat the infection, in case of severe allergies, patients apply a preserved nasal spray three times a day for up to three months. However, preservatives do the exact opposite, slowing down the clearance of the mucus. The German Health Authority (BfArM) recently published a risk statement on the widely used preservative benzalkonium chloride. Patient information leaflets should state that frequent administration of benzalkonium chloride is irritating to the nasal mucosa and that an alternative non-preserved product should be used. The same can be said about benzyl alcohol, which is commonly used as a preservative (see, for example, U.S. Patent No. 8,580,282). The National Library of Medicine's HSDB database notes that benzyl alcohol is irritating to the skin at levels of 3% or higher, and that at a concentration of 0.225 mg / ml in triamcinolone acetonide (TA) after intravitreal injection, benzyl alcohol caused ultrastructural damage and impaired human retinal pigment epithelial cell function in 2 hours.

[0003] Non-preserved nasal products are commonly available as unit-dose and two-dose delivery systems that deliver one or two doses to the nostril. These devices are disposable and therefore do not pose a risk of contamination during their use. Multi-dose systems vary in functional design and require daily use by the patient for up to six months. Non-preserved contents will certainly result in contamination of the drug delivery product during its use.

[0004] Trigeminal neuralgia (TN) is defined by the International Association for the Study of Pain (IASP) as "acute, usually unilateral, severe, brief, lancinating, recurrent attacks of pain in the distribution of one or more branches of the trigeminal nerve". The International Headache Society (IHS) classifies trigeminal neuralgia into two different categories: "classical" and "symptomatic" (secondary) TN. Classical TN includes patients in whom no identifiable cause of TN can be found other than vascular compression of the trigeminal nerve. Symptomatic TN represents patients in whom a cause other than vascular compression can be identified, such as tumor, arteriovenous malformation, or multiple sclerosis (MS). Studies in Europe indicate that trigeminal neuralgia causes considerable interference with daily living activities, comparable to other neuropathic pain conditions, and may lead to suicide.

[0005] There is no specific treatment for trigeminal neuralgia. Treatment is strictly palliative, aimed at symptomatic pain relief, with the goal of treatment being to reduce pain to a tolerable level. Pharmacological treatments currently available for the treatment of symptomatic relief of TN include antidepressants, serotonin noradrenaline reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), antiepileptic drugs, and opioids. In this particular indication, the drug must act rapidly and only locally, but systemic absorption must be as low as possible to avoid systemic side effects associated with typical oral formulations of comparable drug substances. The present invention of intranasal delivery of sodium channel local analgesics provides rapid onset of pain relief and reduced associated side effects. Summary of the Invention [Problem to be solved by the invention]

[0006] Objective and Summary of the Invention It is an object of the present invention to provide formulations and methods that provide pain relief in humans and animals by administration of intranasal doses of preservative-free local anesthetic formulations for the treatment of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headaches. [Means for solving the problem]

[0007] In accordance with these and other objects, the present invention is directed, in part, to a nasal spray formulation of a locally acting sodium channel blocker for treating pain, comprising about 5% to about 30% w / v of a locally active sodium channel blocker, about 0.25% to about 5% w / v of a buffering agent, and about 5 to about 99% w / v of a pharma- ceutically acceptable carrier for nasal administration. The nasal spray formulation is contained in a mechanical multi-dose pump that sprays a unit dose of the nasal spray formulation having a viscosity of 0.8 to about 1.1 cps and having a wide plume and small droplet size, where the unit dose is administered by actuating the mechanical multi-dose pump and spraying a volume of the nasal spray formulation into each nostril of a human subject. The invention is further directed in part to a unit dose of a nasal spray formulation of a locally acting sodium channel blocker for treating pain, comprising about 5% to about 30% w / v of a locally active sodium channel blocker, 0.25% to about 5% w / v of a buffering agent to provide a pH of about pH 4.5 to about pH 7, and about 5 to about 99% w / v of a pharma- ceutically acceptable carrier for nasal administration, wherein the nasal spray formulation has a viscosity of about 0.8 to about 1.1 cps and is contained in a mechanical multi-dose spray pump device, and the unit dose is delivered in a volume of about 0.04 ml to about 0.2 ml as a wide plume defined by an average spray angle of about 50 degrees to about 95 degrees, and small droplet sizes defined by an average Dv10 of about 10 to about 30 μm, an average Dv50 of about 20 to about 60 μm, and an average Dv90 of about 80 to about 120 μm. When sprayed into each nasal cavity of a human patient, the unit dose is therapeutically effective for treating a condition selected from the group consisting of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache. Preferably, each spray administered by actuating a mechanical multi-dose pump provides a volume of about 40 μl to about 120 μl. In certain preferred embodiments, the mechanical multi-dose pump provides a volume of about 100 μl (0.100 ml). When administered in a unit dose intranasally, the nasal spray formulation is therapeutically effective for treating pain associated with a condition selected from the group consisting of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache.In certain preferred embodiments, the locally active sodium channel blocker is a local anesthetic selected from the group consisting of lidocaine, bupivacaine, ropivacaine, mepivacaine, tetracaine, and mixtures of any of the foregoing. In certain preferred embodiments, the nasal spray formulation further comprises a second active agent, such as epinephrine, a vasodilator, an anticonvulsant, a muscle relaxant, an analgesic, and combinations thereof. In certain preferred embodiments, the pharma- ceutically acceptable carrier for nasal administration comprises water. In certain preferred embodiments, the nasal spray formulation, when sprayed, provides a droplet size of about 5 to about 500 microns. In certain preferred embodiments, the locally active sodium channel blocker is lidocaine, and the unit dose provides about 5 mg to about 20 mg of lidocaine sprayed into the nasal cavity of a human subject.

[0008] In a preferred embodiment, the mechanical multi-dose pump includes a spring-loaded valve located directly below the opening of the tip orifice, the mechanical multi-dose pump does not allow microorganisms to migrate into the system from any surface or from liquids it comes into contact with, and / or the mechanical multi-dose pump includes a sterile filtration system including a hydrophobic filter membrane with a pore size of less than 0.2 μm, and the nasal spray formulation does not include a preservative.

[0009] The nasal spray formulation is preferably administered intranasally by spraying about 1-2 sprays into each nostril to provide an effective amount of the locally active sodium channel blocker, providing a total of about 4 sprays per application. When the locally active sodium channel blocker is lidocaine, the intranasal formulation is administered at about 4 hour intervals.

[0010] In certain preferred embodiments, the mechanical multi-dose pump provides small droplet sizes (μm) upon actuation, with an average Dv10 of about 10 to about 30, an average Dv50 of about 20 to about 60, and an average Dv90 of about 80 to about 120. The mechanical multi-dose pump preferably provides an average spray angle of about 50 to about 95 degrees. Preferably, the spray pattern of the multi-dose pump spray has an average Dv of about 10 to about 45 mm.min , D of about 40 to about 70 mm max , providing an ellipticity of about 0.5 to about 2 mm. The ellipticity is D max D min In certain embodiments, the spray pattern of the multi dose pump spray has an area percent of about 12 to about 22 mm.

[0011] The present invention is further directed to a method of treating pain associated with a condition selected from the group consisting of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache, the method comprising incorporating a nasal spray formulation containing a locally active sodium channel blocker to treat pain, the nasal spray formulation comprising from about 5% to about 30% w / v of a locally active sodium channel blocker, from about 0.25% to about 5% w / v of a buffering agent, from about 5 to about 99% w / v of a pharma- ceutically acceptable carrier for nasal administration, the nasal spray formulation being contained in a mechanical multi-dose pump that sprays a unit dose of the nasal spray formulation having a viscosity of from about 0.8 to about 1.1 cps and a wide plume and small droplet size upon actuation, the unit dose being therapeutically effective in treating a condition selected from the group consisting of trigeminal neuralgia, neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache. In certain preferred embodiments, the mechanical multi-dose pump (i) includes a spring-loaded valve located directly below the opening of the tip orifice, preventing the mechanical multi-dose pump from transferring microorganisms into the system from surfaces or liquids it comes into contact with; or (ii) includes a hydrophobic filter membrane with a pore size of less than 0.2 μm; or (iii) both (i) and (ii) above, and the nasal spray formulation does not include a preservative. In certain preferred embodiments, the locally active sodium channel blocker is a local anesthetic selected from the group consisting of lidocaine, bupivacaine, ropivacaine, mepivacaine, tetracaine, and mixtures of any of the foregoing. In certain particularly preferred embodiments, the locally active sodium channel blocker is lidocaine, and the unit dose provides about 5 mg to about 20 mg of lidocaine sprayed into the nasal cavity of a human subject. In certain preferred embodiments, the mechanical multi-dose pump provides a volume of about 0.100 ml. In certain preferred embodiments, the unit dose provides a droplet size of about 5 to about 500 microns. In certain preferred embodiments, the locally active sodium channel blocker is lidocaine and the intranasal formulation is administered at intervals of about 4 hours.In certain preferred embodiments, the unit dose further comprises a second drug selected from the group consisting of an anticonvulsant, a vasodilator, a muscle relaxant, an analgesic that is not a locally active sodium channel blocker, and combinations of any of the foregoing. In certain preferred embodiments, the spray pattern of the mechanical multi-dose pump sprayer preferably has a mean D of about 15 to about 45 mm. min , D of about 40 to about 70 mm max , providing an ellipticity of about 0.5 to about 2 mm, and an area % of about 12 to about 22 mm. In certain preferred embodiments, the wide plume is defined by an average spray angle of about 60 degrees to about 90 degrees, and / or the unit dose is delivered at an average plume width (mm) of about 20 to about 70 mm, and / or the average plume width is about 30 to about 60 mm. In certain preferred embodiments, the pharma- ceutically acceptable carrier for nasal administration comprises water. Certain embodiments of the present invention are directed to the use of the unit dose formulations detailed herein, comprising administering the nasal spray formulation intranasally by actuating a mechanical multi-dose nasal spray pump device to spray one to two sprays into each nostril of a human subject to provide an effective amount of a locally active sodium channel blocker. In certain embodiments, the unit dose of the nasal spray formulation further comprises a second active agent in the nasal spray formulation, the second active agent being selected from the group consisting of epinephrine, vasodilators, anticonvulsants, muscle relaxants, analgesics that are not locally active sodium channel blockers, and combinations of any of the above. In certain preferred embodiments of the method, the unit dose (via a mechanical spray pump device) provides a volume of about 0.04 ml (40 μl) to about 0.2 ml (200 μl) per spray, and in certain embodiments, preferably about 0.08 ml to about 0.12, and in certain embodiments, about 0.10 ml. The nasal spray formulation is preferably administered by actuating a mechanical multi-dose pump to spray about 1 to 2 sprays into each nostril of the human subject, for a total of about 4 sprays per application, providing an effective dose of the locally active sodium channel blocker. When the locally active sodium channel blocker is lidocaine, the intranasal formulation can be administered at intervals of about 4 hours.

[0012] In certain preferred embodiments of the method, a mechanical multi-dose pump is provided such that upon actuation, the mechanical multi-dose pump provides a small droplet size (μm), with an average Dv10 of about 10 to about 30, an average Dv50 of about 20 to about 60, and an average Dv90 of about 80 to about 120. Preferably, the mechanical multi-dose pump provides an average spray angle of about 50 to about 95 degrees. Preferably, the spray pattern of the mechanical multi-dose pump spray has an average Dv of about 15 to about 45 mm. min , D of about 40 to about 70 mm max , an ovality of about 0.5 to about 2 mm, and an area percentage (%) of about 12 to about 22 mm.

[0013] In certain embodiments, a pharma- ceutically acceptable carrier for intranasal administration comprises or consists of water.

[0014] In certain preferred embodiments, the method further comprises configuring a mechanical multi-dose pump to provide a spray droplet size of about 5 to about 500 microns upon actuation.

[0015] In certain preferred embodiments, the drug (e.g., a local anesthetic) comprises about 5 to about 20% w / v of the composition. In certain preferred embodiments, the composition comprises a buffering agent in an amount of about 0% to about 5% w / v of the composition, and in certain preferred embodiments, about 0.25% to about 5% w / v. In certain preferred embodiments, the solvent carrier comprises purified water in an amount of about 5% to about 99% w / v. In certain preferred embodiments, the composition comprises an (optional) preservative in an amount of about 0.25% to about 5% w / v. In certain embodiments, the viscosity of the composition is about 0.8 to about 1.1 cps.

[0016] For purposes of the present invention, the terms "active agent," "drug," and medicament are used interchangeably and are meant to encompass a single drug or multiple drugs (two or more) contained in the nasal spray formulations of the present invention.

[0017] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims should be understood to be modified in all instances by the term "about." Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0018] Whenever a numerical range is given herein, it is meant to include any recited numbers (fractional or integer) within the given range. The phrases "range between" a first indicated number and a second indicated number, and "range from" a first indicated number to a second indicated number (range from the first indicated number to the second indicated number) are used interchangeably herein and are meant to include the first and second indicated numbers and all fractional and integer numbers therebetween.

[0019] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a compound" or "at least one compound" includes a plurality of compounds, including mixtures thereof.

[0020] The term "local anesthetic" means any drug or mixture of drugs that produces localized numbness and / or analgesia.

[0021] The term "unit dose" as used herein refers to physically discrete units suitable as unitary dosages for mammalian subjects, each unit containing a predetermined amount of an active agent (e.g., a local anesthetic) as the active ingredient.

[0022] The term "comprising" as used herein is an inclusive term that is interpreted to mean containing, including, covering or including the elements listed after the term, but does not exclude other unmentioned elements.

[0023] "Therapeutically effective amount" means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for the disease.

[0024] As used herein, the term "treating" or "treatment" of a disease includes preventing the disease from occurring in an animal susceptible to the disease but not yet experiencing or displaying symptoms of the disease (prophylactic treatment), inhibiting the disease (delaying or preventing onset), providing relief from symptoms or side effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease). For purposes of the present invention, "disease" includes pain.

[0025] For purposes of the present invention, the term "active agent" is meant to include, but is not limited to, a drug. The term active agent is further meant to include a single active agent, or multiple (two or more) active agents present in a formulation.

[0026] As used herein, droplet size distribution may be characterized by the following metrics: volume distribution (Dv10, Dv50, Dv90) and span and percentage (%) are less than 9 μm in accordance with FDA CMC Guidance for Nasal Sprays and Inhalation Solutions, Suspensions and Sprays Drug Products - Chemistry, Manufacturing and Control Documents, July 2002. Dv10 means, for example, the diameter at which 10% of the total spray volume is made up of droplets of the same or less diameter. Dv50 means, for example, the diameter at which 50% of the total spray volume is made up of droplets of the same or less diameter. Dv90 means, for example, the diameter at which 90% of the total spray volume is made up of droplets of the same or less diameter.

[0027] As used herein, D max is defined as the longest diameter measured on the resulting spray pattern image.

[0028] As used herein, D minis defined as the shortest diameter measured on the resulting spray pattern image.

[0029] For purposes of the present invention, the spray pattern may be characterized by one or more of the following metrics: D, in accordance with FDA Guidance for Industry: Bioavailability and Bioequivalence Testing for Nasal Aerosols and Nasal Sprays for Local Action. max , D min , ellipticity, and area%.

[0030] As used herein, ellipticity is D max Against D min This ratio provides a quantitative value for the overall shape of the spray.

[0031] As used herein, spray angle means the angle of the discharge plume measured from the apex of the spray cone and spray nozzle in accordance with FDA guidance for industry.

[0032] As used herein, plume width means the width of the plume at a given distance from the spray nozzle, in accordance with FDA guidance for industry.

[0033] For purposes of the present invention, all percentages stated herein are "w / w" unless otherwise specified. [Brief description of the drawings]

[0034] [Figure 1] FIG. 1 is a graph showing the mean pharmacokinetic profiles of the lidocaine intranasal sprays of Examples 4 and 5.

[0035] [Diagram 2] FIG. 2 is a graph of the amplitude of rubbing at the formalin injection site 45 minutes after formalin administration in the test formulations of Examples 4 and 5 versus placebo in treated rabbits. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] The present invention in certain embodiments is directed to a method of treating pain comprising administering a preservative-free intranasal composition in multiple or double doses or unit dose sprays via utilization of a (mechanical pump) metered dose spray device.

[0037] The present invention relates to a preservative-free, multi-dose and / or unit dose and / or double dose nasal spray formulation of an aqueous local anesthetic (e.g., a sodium channel blocker such as lidocaine), the formulation comprising droplets of lidocaine, a pharma- ceutically acceptable salt, or derivative thereof; and a pharma- ceutically acceptable solvent carrier, the droplets having a size distribution of about 5 microns to about 500 microns.The present invention relates to a method of treating pain comprising the use of a spray device.

[0038] The present invention discloses a (preferably) preservative-free intranasal composition in a multi-dose or double-dose or unit dose spray container for treating pain associated with trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache. In certain embodiments, the intranasal spray formulation of the present invention can be used to treat generalized pain, neuropathic pain (e.g., erythromelalgia, postherpetic neuralgia (PHN), fibromyalgia, and / or complex regional pain syndrome (CRPS), etc.).

[0039] Liquid pharmaceutical compositions of the present invention comprise a pharma- ceutically effective amount of a sodium channel blocker (e.g., lidocaine) in a pharma- ceutically acceptable liquid carrier, e.g., purified water, and an optional buffering agent, e.g., citrate, to maintain a pH between 3 and 8, preferably between 3 and 6, and an optional complexing agent, e.g., citrate or EDTA, to inhibit precipitation of the drug substance from the aqueous medium.

[0040] Lidocaine (xylocaine) was introduced as a local anesthetic in 1948. Local anesthetics act by interfering with the generation and conduction of nerve impulses. Their primary site of action is the cell membrane. They block conduction by reducing or preventing the large, transient increase in the permeability of excitable membranes to Na+ that is normally produced by a slight depolarization of the membrane. This action of local anesthetics is due to a direct interaction with voltage-gated Na+ channels. As anesthesia gradually develops in a nerve, the threshold for electrical excitation gradually increases, the rate of rise of the action potential decreases, impulse conduction slows, and the safety factor of conduction decreases. These factors decrease the likelihood of propagation of the action potential and nerve conduction fails. Bupivacaine, a longer-acting variant of lidocaine, is the preferred local analgesic.

[0041] The degree of block produced by a given concentration of local anesthetic depends on how the nerve is stimulated and its resting membrane potential. Thus, resting nerves are much less sensitive to local anesthetics than nerves that are repeatedly stimulated. The more frequent the stimulation and the higher the membrane potential, the greater the anesthetic block. These frequency- and voltage-dependent effects of local anesthetics occur because the charged form of the local anesthetic molecule has access to the binding site in the pore only when the Na+ channel is in the open state, and because the local anesthetic molecule binds more tightly to the Na+ channel, stabilizing the inactivated state of the Na+ channel. Local anesthetics exhibit these properties to different degrees, depending on their pKa, lipid solubility, and molecular size.

[0042] The Lidoderm patch is cumbersome to use. It is provided in a 10 cm x 14 cm patch. Patients are instructed to apply three patches at a time to the most painful area for up to 12 hours. According to the package insert, erythema, edema, bruising, papules, blisters, discoloration, depigmentation, burning, itching, and abnormal sensations that return when the patch is removed may appear at the patch site. The patch is not patient friendly when the pain appears outside the upper body and trunk area, especially in the facial area (myofascial pain). The present invention is expected to be an easy-to-use unique skin spray formulation to overcome many of the disadvantages of patch application while providing pain relief for PHN patients. The intranasal formulation offers convenience of application.

[0043] In certain preferred embodiments of the present invention, a therapeutically effective amount of one or more pharma- ceutically acceptable local anesthetics are incorporated into the formulations of the present invention. Examples of local anesthetics useful in the formulations of the present invention include amide-type local anesthetics such as mepivacaine, lidocaine, mepivacaine, etidocaine and prilocaine, ester-type local anesthetics such as procaine, chloroprocaine and tetracaine, and antihistamine-like anesthetics such as benadryl. These anesthetics can be present in the anesthetic combination alone or as a mixture of two or more of them. Thus, examples of useful local anesthetics are lidocaine, bupivacaine, dibucaine, tetracaine, etidocaine, mepivacaine, ropivacaine, benzocaine, ambucaine, amylocaine, butambene, 2-chloroprocaine, cyclomethycaine, ethyl aminobenzoate, euprosin, levoxadrol, orthocaine, piperocaine and parethoxycaine. In certain preferred embodiments, the local anesthetic is bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, and xylocaine, or mixtures thereof. The phrase "local anesthetic" also includes classes of drugs other than those traditionally associated with local anesthetic properties, such as morphine, fentanyl, and drugs that can provide local blockade of nociceptive pathways (afferent and / or efferent). In other embodiments, the active agent is an anesthetic such as a barbiturate (e.g., amobarbital, methohexital, thiamylal, thiopental), a benzodiazepine (e.g., diazepam, lorazepam, midazolam), or etomidate, ketamine, or propofol. Other compounds that can be used as local anesthetics in the gel formulations of the present invention include antihistamine-like anesthetics such as benadryl. Phenol may also be used as a local anesthetic. Those skilled in the art will recognize other drugs that are recognized to have local anesthetic properties, such as the substituted piperidines and pyrrolidines described in U.S. Pat. No. 4,302,465 (Aberg, et al.) and the aminoindan piperidine compounds described in U.S. Pat. No. 6,413,987 (Aberg, et al.).Both of these patents are incorporated herein by reference. The term local anesthetic is also considered for purposes of this invention to include local anesthetic bases or pharma- ceutically acceptable salts, polymorphs, complexes, or prodrugs thereof. Many other examples of both drugs and local anesthetics will be readily apparent to those of skill in the art and are considered to be within the scope of this disclosure and the appended claims.

[0044] The local anesthetic may be in the form of a salt, such as a hydrochloride, bromide, acetate, citrate, carbonate, sulfate, or phosphate. In certain embodiments, the local anesthetic is in the form of a free base. The local anesthetic may be in the form of a salt, such as a hydrochloride, bromide, acetate, citrate, carbonate, or sulfate, or in the form of a free base. Many local anesthetics are typically used in the form of an acid addition salt. This provides solubility in aqueous injection media. In certain embodiments of the invention, it is desirable to use the local anesthetic in free base form or with only a small amount of an acid addition salt of the local anesthetic present (adding a small amount of an acid addition salt, if necessary, may enhance release). The free base typically provides a slow initial release, avoiding premature "damping" of the local anesthetic at the injection site. Preferred local anesthetics include, for example, lidocaine, bupivacaine, or ropivacaine.

[0045] In certain preferred embodiments, the dose of local anesthetic contained in the unit dose is about 1 mg to about 30 mg based on the unit dose of lidocaine. In other preferred embodiments, the dose is about 5 mg to about 20 mg, preferably about 5 mg to about 15 mg. In certain preferred embodiments, the unit dose of local anesthetic is 10 mg of lidocaine, or a therapeutically equivalent amount of another local anesthetic. Those skilled in the art will understand how to determine equipotent doses of local anesthetics. The maximum doses and durations of action of the following local anesthetics are generally accepted: lidocaine - 4.5 mg / kg, duration 0.75-1.5 hours; mepivacaine - 4.5 mg / kg, duration 1-2 hours; prilocaine - 8 mg / kg, duration 0.5-1 hour; bupivacaine 3 mg / kg, duration 1.5-8 hours; ropivacaine 3 mg / kg, duration 1.5-8 hours; chloroprocaine - 12 mg / kg, duration 0.5-1 hour; procaine 12 mg / kg, duration 0.5-1 hour; cocaine - 3 mg / kg, duration 0.5-1 hour. Tetracaine - 3 mg / kg, duration 1.5-6 hours.

[0046] In the present invention, nasal sprays were prepared by adding the drug, optional buffer, to the solvent while stirring the solution to ensure complete dissolution of the drug and excipients. The formulations were stored in tightly sealed glass vials with a metering spray pump.

[0047] In certain preferred embodiments, the active agent (drug) is a therapeutically effective amount of a combination of two different local anesthetics (eg, a combination of bupivacaine and lidocaine) for use in the treatment of pain.

[0048] The composition preferably contains about 1% to about 30% w / v of at least one pharmaceutical (drug), more preferably about 5% to about 20% w / v of at least one drug, and most preferably about 10% w / v of at least one drug.

[0049] In certain preferred embodiments, the drug is supersaturated in the formulation, it is believed that the closer the drug is to being supersaturated in the formulation, the more penetration will result when the drug is administered, for example, by spraying into the nasal passages.

[0050] In certain preferred embodiments, the active agent (drug) is a combination of a therapeutically effective amount of a local anesthetic (e.g., lidocaine) and ketamine and / or amitriptyline for use in the treatment of pain. In certain embodiments, the active agent includes a combination of lidocaine hydrochloride and a second active agent selected from the group consisting of ketamine, amitriptyline, and combinations thereof. In certain preferred embodiments, the active agent (drug) is a combination of a therapeutically effective amount of a local anesthetic (e.g., lidocaine) and meloxicam and / or other muscle relaxants for use in the treatment of pain. In certain embodiments, the active agent includes a combination of lidocaine hydrochloride and a second active agent selected from the group consisting of meloxicam, tizanidine, and combinations thereof.

[0051] In certain preferred embodiments, the active agent (drug) is a therapeutically effective amount of a local anesthetic (e.g., lidocaine) in combination with epinephrine and / or a vasodilator for use in the treatment of pain. In certain embodiments, the active agent comprises lidocaine hydrochloride in combination with a second active agent selected from the group consisting of epinephrine, vasodilators, and combinations thereof. Suitable vasodilators include, but are not limited to, diltiazem, clonidine, nifedipine, verapamil, isosorbide-5-mononitrate, organic nitrates, drugs used in the treatment of cardiac disease, and analogs thereof.

[0052] In certain preferred embodiments, the active agent (drug) is a therapeutically effective amount of a local anesthetic (e.g., lidocaine) in combination with carbamazepine and / or an anticonvulsant for use in treating pain. In certain embodiments, the active agent comprises a combination of a local anesthetic (e.g., lidocaine hydrochloride) and a second active agent selected from the group consisting of carbamazepine, an anticonvulsant, and combinations thereof.

[0053] The formulations of the present invention may also contain two or more of the above components (drugs) or pharma- ceutically acceptable salts, complexes or derivatives thereof.

[0054] Optional Excipients In addition to the active agent (e.g., a local anesthetic), the nasal spray formulations may further include physiologically acceptable components such as sodium chloride and similar substances conventionally used to achieve isotonicity with typical body fluids, pH buffers to establish a physiologically compatible pH range and to enhance solubility of any anesthetics present, vasodilators such as epinephrine, preservatives, stabilizers, antioxidants, and the like.

[0055] In certain other embodiments, additional surfactants (co-surfactants) and / or buffers may be preferably combined with one or more pharma- ceutically acceptable vehicles as described hereinabove, such that the surfactants and / or buffers maintain the product at an optimal pH for stability. The surfactants and / or buffers may also prevent the initial stinging or burning discomfort associated with administration of an active agent (e.g., a local anesthetic) to the skin.

[0056] In certain other embodiments, additional antioxidants and / or stabilizers may be preferably combined with one or more pharma- ceutically acceptable vehicles as described hereinabove, where the antioxidants and / or stabilizers maintain the drug product at optimal impurity levels for stability. The antioxidants and / or stabilizers also prevent early degradation of the active agent during the manufacturing process. The antioxidants may be selected from, for example, ascorbic acid, EDTA, trolamine, tocopherol, propyl gallate, sodium sulfite, sodium bisulfate, and mixtures thereof. The optional stabilizer may be, for example, an antioxidant and / or a pH adjuster. In other embodiments, the optional stabilizer may be cyclodextrin used as an inclusion complex. Pharmaceutically acceptable pH adjusters include, by way of example, but are not limited to, hydrochloric acid, citric acid, sodium acetate, sodium hydroxide, sodium phosphate, or lactic acid. In certain embodiments, a buffer selected from, for example, citric acid monohydrate, acetate buffers (e.g., sodium acetate, ammonium acetate), and succinate buffers is included, preferably to maintain the formulation at a pH of about 3 to about 9, and in certain preferred embodiments, about pH 4.5 to about pH 7, or about pH 5.5. In certain preferred embodiments, the injectable formulations preferably have a pH in the physiologically compatible pH range, for example, after dilution with water and / or other commonly available solutions suitable for intranasal application.

[0057] Optional antimicrobial agents, either bacteriostatic or at bacteriostatic concentrations, may be added to the formulations packaged in multi-dose containers, including phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid, p-hydroxybenzoates, phenols, chlorinated phenolic compounds, alcohols, quaternary compounds, mercurials, mixtures thereof, and the like. Optional isotonicity agents include, by way of example and without limitation, sodium chloride and dextrose. Optional suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Optional emulsifying agents include polysorbate 80 (TWEEN® 80). Pharmaceutically acceptable pH adjusting agents include, by way of example and without limitation, sodium hydroxide, hydrochloric acid, citric acid, or lactic acid. In some embodiments of the invention, the pH is adjusted using a pharma- ceutically acceptable buffer or acidifier, particularly when the active agent is in its base form (eg, lidocaine base).

[0058] In certain other embodiments, the formulation can be made isotonic through the addition of a tonicity agent conventionally used to achieve isotonicity with typical body fluids, a pH buffer to establish a physiologically compatible pH range, such as, but not limited to, any pharma- ceutically acceptable sugar, salt, or any combination or mixture thereof, such as, but not limited to, dextrose and sodium chloride. The tonicity agent can be present in an amount of about 100 mOsm / kg to about 500 mOsm / kg, or about 200 mOsm / kg to about 400 mOsm / kg, or about 280 mOsm / kg to about 320 mOsm / kg.

[0059] In certain preferred embodiments, the formulation of the invention has the following composition (% w / w): Activator 5-20%w / v Buffer 0.25-5% w / v Purified water 5-99%w / v Preservative (optional) 0.25‐5w / v Viscosity: 0.8-1.1cps

[0060] The formulations of the present invention may contain a preservative to prevent the growth of microorganisms. Preservatives suitable for use in the present invention include, but are not limited to, benzoic acid, boric acid, p-hydroxybenzoates, phenols, chlorinated phenolic compounds, alcohols, quaternary compounds, mercurials, mixtures thereof, and the like.

[0061] Preservative-free formulation When using a preservative-free multi-dose product, there are two ways for microorganisms to enter the system: (1) through the pump opening; and (2) through the vent air that replaces the delivered liquid. In a preserved formulation (conventional system), the added preservative controls the growth of microorganisms and no additional measures need to be taken to prevent the entry of microorganisms through the opening or vent. If the formulation does not contain a preservative, the device must be able to keep microorganisms out of the system. The highest risk of infection is usually the opening. This is because the opening can come into contact with infected body fluids as well as the skin and mucous membranes.

[0062] To prevent microbial contamination in the present invention, certain preferred embodiments of the pump opening include a mechanical approach to minimize interactions between the device parts and the formulation. For example, in certain preferred embodiments, a spring-loaded valve is placed directly under the tip opening opening to not allow microorganisms to migrate from the surface or contact liquid into the system. Thus, the opening is "sealed" at rest. The tip seal keeps the system closed until the system is actuated to reach a defined pressure. The system then opens and the formulation is forced out of the opening at a pressure higher than that required to open the valve. When the pressure drops at the end of the actuation, the tip seal moves outward, immediately closing the opening. This prevents backflow of potentially contaminated medicine or other liquids.

[0063] In an additional or alternative embodiment, to prevent microbial contamination, microbial contamination of the formulation is avoided by venting air using a sterile filtration system. The vent air of the pressure balance system is forced through a sterile filter with a pore size of less than 0.2 μm. The filter membrane is typically hydrophobic, preventing liquid from leaking from the container through the vent system.

[0064] During the manufacturing process, the drug product solution (formulation) is preferably sterilized and the filling and assembly of the spray pump is carried out under aseptic conditions to avoid microbial contamination during drug product manufacturing and packaging.

[0065] mechanical sprayer In certain preferred embodiments, the compositions of the present invention are sprayed into the nostrils of a subject (e.g., a human patient) via a mechanical multi-dose pump having an average spray volume, e.g., about 40 μl to about 120 ul. Preferably, the multi-dose pump sprays with a wide plume and small droplet size. A representative multi-dose pump that is useful is the Pfeiffer SAP-62602 multi-dose pump (130 ul / actuation) (Pfeiffer, Princeton, NJ). For purposes of the present invention, "wide plume" means that the spray pump pattern has an average spray angle, preferably about 50 degrees to about 95 degrees, more preferably about 60 degrees to about 90 degrees, and most preferably about 70 degrees to about 80 degrees; and an average plume width (mm) of about 20 to about 70 mm, more preferably about 30 to about 60 mm, and most preferably about 42 to about 52 mm. For the purposes of the present invention, the term "small droplet size" refers to a droplet size (μm) having an average Dv10 of about 10 to about 30, an average Dv50 of about 20 to about 60, and an average Dv90 of about 80 to about 120. The spray pattern of a multi-dose pump spray is preferably from about 15 to about 45 mm with an average Dv of about 15 to about 45 mm. min , D of about 40 to about 70 mm max , an ovality of about 0.5 to about 2 mm, and an area percentage of about 12 to about 22 mm.

[0066] In a particular preferred embodiment of the present invention, a multi-dose pump (metering device) is used having the characteristics described in US Patent Publication No. 2007 / 026090A1, the disclosure of which is incorporated herein by reference in its entirety. For example, a metering device for at least one medium, comprising a pump unit operatively connected to a medium reservoir for the purpose of discharging the medium, and a venting device assigned to the medium reservoir and / or to the pump unit, with a vent channel to which a filter membrane is assigned. Therein, a metering device is described in which the filter membrane has a reduced effective cross-sectional area compared to known filter membranes. The effective cross-sectional area is the product of the number of pores provided in the filter membrane and the average free cross-sectional area of ​​these pores. The filter membranes are designed in particular as stretched or perforated plastic films or sintered materials, but also as metal foils, and can vary in wide ranges in terms of the number of pores and the free cross-sectional area of ​​the pores, depending on the selected manufacturing method. The pores or channels formed in the plastic film or sintered material, respectively, have a free cross-sectional area that can be determined based on the maximum molecular size that can pass through the channel. The effective cross-sectional area is directly related to the diffusion rate of the filter membrane. A large number of channels or pores and a large free cross-sectional area of ​​each individual channel or pore provides a large effective cross-sectional area, allowing a high diffusion rate; that is, a large number of molecules can pass through the filter membrane at a low pressure difference. In certain preferred embodiments, the effective surface area of ​​the filter membrane is 1.4 mm 2 Less than 0.6mm, preferably 2 Less than 0.2 mm, particularly preferably 2 In another embodiment, to obtain a reduced effective cross-sectional area, the mean free cross-sectional area of ​​the pores of the filter membrane is designed to be smaller than that of known filter membranes. This means that the size of gas molecules that can pass through the filter membrane is reduced. In another embodiment, the filter membrane is less than 1 mm 2 Less than 1 million pores per mm, preferably 1 mm 2 Less than 600,000 pores per mm, particularly preferably 1 mm 2 The average pore number per unit area is less than 300,000 pores.

[0067] In a particular preferred embodiment of the invention, a multi-dose pump (metering device) is used having the characteristics described in US Pat. No. 8,382,010, the disclosure of which is incorporated herein by reference in its entirety. This US patent describes a dosing device with a manually actuable pumping means, a pump chamber, and an injection valve configured as a slide valve, which is movable by a dosing stroke in a sealed state in a dosing channel in a closed position, defining a dosing volume in the pump chamber, the dosing channel opening into the injection area on the injection side. The device preferably further comprises at least one gas flow capillary, which has one end open to the environment and the other end leading to a medium reservoir, the end facing said medium reservoir being provided with a filter unit. This allows the medium reservoir to be ventilated without causing contamination of the medium by ambient air. In certain preferred embodiments, the multi-dose pump includes a manually actuable pump device having a pumping chamber and an injection valve constructed as a slide valve having a cylindrical dosing channel consisting of an upper portion and a lower portion, the upper portion and the lower portion being coaxially aligned with a pumping axis, a wall surface of the lower portion having circumferentially spaced flow profiles, and a piston having a sealing lip configured to slide along the length of the dosing channel along the pumping axis while sequentially slidingly engaging the upper and lower wall surfaces of the dosing channel, the injection side of the dosing channel opening into a lower dosing area remote from the upper portion, the injection area being connected to a sealing lip. The sealing lip has flow profiling configured to cause opening of the slide valve upon movement of the sealing lip into the infusion region, the sealing lip is in a closed position of the slide valve while sealingly slidingly engaging the upper wall surface and opens in response to the sealing lip engaging the lower infusion region caused by the flow profiling, thereby allowing media to flow past the sealing lip from the media reservoir through the flow profiling into the dosing channel and into the pump chamber, the sealing lip being sealingly movable along the pumping axis over a dosing stroke in the dosing channel such that the slide valve defines a dosing volume for the pump chamber.Preferably, the flow profiling is formed by longitudinal grooves oriented in the longitudinal direction of the dosing stroke and extending parallel to the pumping axis over the axial length of the dosing area, the flow profiling being arranged in a uniformly distributed manner with respect to one another in the circumferential direction of the dosing area. In a particular preferred embodiment, the dosing area and the dosing channel are provided on separate components. The components are joined to one another in a preferably coaxially interengaging manner, on opposing circumferential surfaces the components are profiled such that between the circumferential surfaces at least one gas flow capillary is formed between the axially facing leading edges of the circumferential surfaces. Preferably, the gas flow capillary has a first end opening into the environment outside the device and a second end opening into the medium reservoir, the second end facing the medium reservoir and provided with a filter unit.

[0068] treatment The intranasal formulations of the present invention can be packaged in multi-dose or bi-dose or unit dose spray containers for treating pain associated with trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine headaches, and cluster headaches.

[0069] When the intranasal formulation includes a local anesthetic (e.g., lidocaine, bupivacaine, ropivacaine, mepivacaine, tetracaine, alone and / or in combination), the mechanical sprayer device preferably delivers a volume of, for example, about 0.04 ml to about 0.12 ml, or about 0.10 ml. In such instances, the formulation can be administered intranasally by spraying one or two times into each nostril for a total of about four sprays in each application (to provide an effective dose). When the drug is lidocaine, the intranasal formulation is administered, for example, at about four hour intervals.

[0070] In certain preferred embodiments, the treatment further comprises administering a second active agent selected from the group consisting of epinephrine, vasodilators, anticonvulsants, muscle relaxants, analgesics that are not locally active sodium channel blockers, and any combination of the above.Preferably, the second active agent is incorporated into a nasal spray formulation.However, the second active agent can be administered separately, simultaneously, or sequentially, for example, with the local anesthetic. EXAMPLES

[0071] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples according to the present invention should not be construed as limiting the invention in any manner, but are merely samples of the various formulations described herein.

[0072] Examples 1-3 A preservative-free lidocaine intranasal formulation is prepared using the ingredients shown in Table 1. [Table 1]

[0073] The formulation is prepared as follows: Citric acid monohydrate is added to purified water with stirring and mixed until a clear solution is observed. Lidocaine base or salt and other optional excipients are added with stirring and mixed for 30 minutes until a clear solution is formed. Filter the clear solution using a sterile 0.2 micron pore size filter and aseptically fill glass bottles with the solution and crimp a metered dose mechanical pump tightly.

[0074] Examples 4-5 A preservative-free lidocaine intranasal formulation is prepared using the ingredients shown in Table 2. [Table 2]

[0075] The formulation is prepared as follows: Citric acid monohydrate is added to purified water with stirring and mixed until a clear solution is observed. Lidocaine base or salt and other optional excipients are added with stirring and mixed for 30 minutes until a clear solution is formed. Filter the clear solution using a sterile 0.2 micron pore size filter and aseptically fill glass bottles with the solution and crimp a metered dose mechanical pump tightly. The droplet size distribution of the intranasal spray of Example 5 is shown in Table 3. [Table 3]

[0076] Examples 6-8 Preservative-free intranasal formulations of lidocaine in combination with other drugs are prepared using the ingredients shown in Table 4 for Examples 6-8. [Table 4]

[0077] The formulation is prepared as follows: add citric acid monohydrate to purified water with stirring and mix until a clear solution is observed. Add lidocaine base or salt, concomitant medication, and other optional excipients with stirring and mix for 30 minutes until a clear solution is formed. Filter the clear solution using a sterile 0.2 micron pore size filter and aseptically fill glass bottles with the solution and crimp a metered dose mechanical pump tightly.

[0078] Example 9 (In vivo test) In vivo studies were conducted in healthy rabbits to evaluate drug release from lidocaine nasal sprays made according to Examples 4 and 5. A single dose study to evaluate the pharmacokinetics of two different formulations (Examples 4 and 5) and to access local anesthetic activity, 10 mg lidocaine per spray (intranasal spray formulation), 0.10 ml per spray. A total of 18 New Zealand White rabbits (both male and female) were used. The rabbits were randomized and divided into three groups (group 1 represents the formulation of Example 5, group 2 represents the formulation of Example 4, and group 3 represents the placebo formulation). There were six rabbits in each group (3 males and 3 females).

[0079] The test formulation was administered as a single spray into each nostril using a metered spray pump (a total of two sprays equals 20 mg of lidocaine). 15 minutes after administration of the test formulation, 100 μl of 5% formalin solution was administered subcutaneously to the rabbits near the center of the nose on the right cheek and housed individually in a test box. The rabbits were observed for 45 minutes (post-formalin administration). Pain scores were determined by measuring the number of seconds (amplitude) the animals spent rubbing the injected area, i.e., the right cheek. To determine the pharmacokinetics of the test formulation, blood samples were taken from each rabbit at 0, 0.08, 0.25, 0.5, 0.75, 1, 2, 4, 8, and 24 hours after administration of the test formulation.

[0080] The compositions were sprayed using a Pfeiffer SAP-62602 multi-dose pump (130 μL / actuation) (Pfeiffer, Princeton, NJ).

[0081] The plasma concentration-time profiles of lidocaine following intranasal (Examples 4 and 5) and placebo routes of administration, as well as individual and mean pharmacokinetic parameters, are shown in Table 5. The mean pharmacokinetic (plasma concentration-time) profiles are shown in FIG.

[0082] Lidocaine plasma concentrations were found to be below the LLOQ in placebo group #3 and were not considered in the estimation of PK parameters.

[0083] Group 1 (Example 5): The mean Cmax was found to be 724 ng / mL with a median Tmax of 0.25 hours. Mean AUC 0-t and AUC 0-infinity were found to be 964 and 99 ng*hr / ml, respectively. The mean elimination half-life was found to be 0.998 hours. The clearance and volume of distribution were 345 ml / min and 29.2 L, respectively.

[0084] Group 1 (Example 4): The mean Cmax was found to be 808 ng / mL with a median Tmax of 0.25 hours. AUC 0‐t and AUC 0‐infinity were found to be 979 and 1010ng*hr / m, respectively. The mean elimination half-life was found to be 0.928 hours. The clearance and volume of distribution were 345ml / min and 27L, respectively. [Table 5]

[0085] Formalin stimulation test The total amplitude of the measured behavior (total time spent rubbing the formalin injection site) was found to be 27.91, 53.78, and 81.83 seconds for test formulations Ex. 5, Ex. 4, and placebo, respectively. The mean amplitude was found to be 4.65, 8.96, and 13.64 seconds for test formulations Ex. 5 (identified as Test Formulation 1 in FIG. 2), Ex. 4 (identified as Test Formulation 2 in FIG. 2), and placebo (identified as Test Formulation 3 in FIG. 2), respectively. For comparison of test formulations Ex. 4 and Ex. 5 with the placebo formulation, the data was statistically analyzed using an unpaired t-test. The amplitude of the rubbing behavior is shown in FIG. 2. A significant decrease in formalin-induced pain / irritation scores was observed for both test formulations Ex. 4 and Ex. 5 when compared with the placebo formulation.

[0086] Example 10 (Stability Data) In Example 10, 5 ml glass bottles were filled with the formulations of Example 4 (base) and Example 5 (hydrochloride) using a metering spray pump and subjected to stability under the following conditions: ICH accelerated conditions (ACC) at 40°C ± 2°C / 75% RH ± 5% RH; and ICH room temperature conditions (CRT) at 25°C ± 2°C / 60% RH ± 5% RH.

[0087] The International Conference on Harmonisation ("ICH") is a project bringing together regulatory authorities and pharmaceutical industry experts from Europe, Japan and the United States.

[0088] Samples were analyzed to determine lidocaine assay, impurities and physical stability (drug precipitation, color change and pH). The stability data is shown in Tables 6 and 7 below. [Table 6] [Table 7]

[0089] conclusion The examples provided above are not meant to be exhaustive, and many other variations of the invention will be apparent to those skilled in the art and are contemplated to be within the scope of the appended claims.

[0090] The active agent may be incorporated into the intranasal formulation in a therapeutically equivalent amount. The actual dose (relative efficacy) of the active agent may be determined based on a comparative dose to the therapeutically effective dose of the active agent described herein.

Claims

1. 1. A nasal spray formulation of a locally active sodium channel blocker for use in the treatment of pain associated with a condition selected from the group consisting of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache, comprising: the nasal spray formulation consists of 5%-30% w / v of a locally active sodium channel blocker or a pharma- ceutically acceptable salt thereof, 0.25%-5% w / v of a buffering agent, an optional second active agent selected from the group consisting of epinephrine, ketamine, a vasodilator, an anticonvulsant, a muscle relaxant, and any combination thereof, and 5-99% w / v of a pharma- ceutically acceptable carrier for nasal administration; the nasal spray formulation has a viscosity of 0.8 to 1.1 cps; said use comprising spraying a unit dose of said nasal spray formulation with a wide plume from a mechanical multi-dose spray pump device to provide a mean spray angle of 50-95 degrees and a small droplet size having a mean Dv10 of 10-30 μm, a mean Dv50 of 20-60 μm and a mean Dv90 of 80-120 μm; The nasal spray formulation, wherein when sprayed into the nasal cavity of a human patient, the unit dose is therapeutically effective to treat a condition selected from the group consisting of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine headache, and cluster headache.

2. 1. A nasal spray formulation of a locally active sodium channel blocker for use in the treatment of pain associated with a condition selected from the group consisting of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache, comprising: The nasal spray formulation comprises 5%-30% w / v of a second active agent selected from the group consisting of a locally active sodium channel blocker, epinephrine, ketamine, a vasodilator, an anticonvulsant, a muscle relaxant, and any combination thereof, 0.25%-5% w / v of a buffering agent, and 5-99% w / v of a pharma- ceutically acceptable carrier for nasal administration; the nasal spray formulation has a viscosity of 0.8 to 1.1 cps; said use comprising delivering a unit dose of said nasal spray formulation from a mechanical multi-dose spray pump device as a volume of 0.04 ml to 0.2 ml, a wide plume defined by an average spray angle of 50 to 95 degrees, and small droplet sizes defined by an average Dv10 of 10 to 30 μm, an average Dv50 of 20 to 60 μm, and an average Dv90 of 80 to 120 μm; The nasal spray formulation, wherein when sprayed into each nostril of a human patient, the unit dose is therapeutically effective to treat a condition selected from the group consisting of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine headache, and cluster headache.

3. 3. The nasal spray formulation of claim 1 or 2, wherein the mechanical multi-dose pump provides a volume of 0.100 ml.

4. 3. The nasal spray formulation of claim 1 or 2, wherein the locally active sodium channel blocker is lidocaine and the intranasal formulation is administered at four hourly intervals.

5. 10. The nasal spray formulation of claim 1, wherein the unit dose comprises a second active agent.

6. 3. The nasal spray formulation of claim 1 or 2, wherein said use provides a spray droplet size of 5 to 500 microns.

7. The spray pattern of the mechanical multiple dose spray pump device has an average D of 15 to 45 mm. ｍｉｎ , 40 to 70 mm D ｍａｘ 3. The nasal spray formulation of claim 1 or 2, providing a viscosity of 0.01 to 0.1 mmHg, and an ellipticity of 0.5 to 2.

8. 3. The nasal spray formulation of claim 1 or 2, wherein the broad plume is defined by an average spray angle of between 60 degrees and 90 degrees.

9. 3. The nasal spray formulation of claim 1 or 2, wherein the unit dose is sprayed or delivered with an average plume width (mm) of 20 to 70 mm.

10. 10. The nasal spray formulation of claim 9, wherein the average plume width is from 30 to 60 mm.

11. 6. The nasal spray formulation of claim 1, 2 or 5, wherein the locally active sodium channel blocker is lidocaine or a pharma- ceutically acceptable salt thereof, and wherein a unit dose of the nasal spray formulation provides from 5 mg to 20 mg of lidocaine or a pharma- ceutically acceptable salt thereof.

12. 6. The nasal spray formulation of claim 1 or 5, wherein the locally active sodium channel blocker is selected from the group consisting of lidocaine, mepivacaine, bupivacaine, ropivacaine, chloroprocaine, procaine, tetracaine, or a pharma- ceutically acceptable salt thereof, and any combination thereof.

13. 10. The nasal spray formulation of claim 1, wherein the pharma- ceutically acceptable carrier for nasal administration comprises water.

14. 10. The nasal spray formulation of claim 1, wherein the mechanical multi-dose spray pump device provides a volume of from 0.04 ml to 0.2 ml upon actuation and the locally active sodium channel blocker is supersaturated in the formulation.

15. 3. The nasal spray formulation of claim 2, wherein the locally active sodium channel blocker is lidocaine or a pharma- ceutically acceptable salt thereof and the second active agent is epinephrine or a pharma- ceutically acceptable salt thereof.

16. 3. The nasal spray formulation of claim 2, wherein the locally active sodium channel blocker is lidocaine or a pharma- ceutically acceptable salt thereof and the second active agent is selected from the group consisting of ketamine, a vasodilator, an anticonvulsant, a muscle relaxant, and any combination thereof.

17. 10. The nasal spray formulation of claim 1, wherein the buffering agent is in an amount sufficient to provide a pH of the nasal spray formulation of from pH 4.5 to pH 7.

18. 3. The nasal spray formulation of claim 2, wherein the delivery is by intranasally administering the nasal spray formulation by actuating the mechanical multi-dose spray pump device and spraying 1-2 sprays into each nostril of a human subject to provide an effective dose of the locally active sodium channel blocker.

19. 3. The nasal spray formulation of claim 1 or 2, wherein the locally active sodium channel blocker is lidocaine or a pharma- ceutically acceptable salt thereof.

20. 3. The nasal spray formulation of claim 1 or 2, wherein said use provides a median Tmax of 0.25 hours.

21. 3. The nasal spray formulation of claim 1 or 2, wherein the mechanical multiple dose pump device includes a spring-loaded valve located directly below the tip orifice opening such that the mechanical multiple dose pump does not transfer microorganisms from a surface or liquid in contact with the mechanical multiple dose pump into the system of the device, and / or the mechanical multiple dose pump device includes a sterile filtration system including a hydrophobic filter membrane having a pore size of less than 0.2 μm.

22. 3. The nasal spray formulation of claim 1 or 2 for use in treating pain associated with a condition selected from the group consisting of trigeminal neuralgia, facial neuropathic pain, and facial cancer-induced neuropathic pain.

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