Therapeutic composition of intranasal lidocaine

Abstract

To provide formulations for providing pain relief in humans and animals by administering a preservative-free intranasal dose of a local anesthetic formulation for the treatment of tri-geminal neuralgia, facial neuropathic pain, facial cancer induced neuropathic pain, migraine pain, and cluster headache pain.SOLUTION: A nasal spray formulation comprises 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, and from 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 which sprays a unit dose of the nasal spray formulation with a wide plume and small droplet size, and the unit dose is administered by actuating the mechanical multi-dose spray pump device and spraying a certain amount of the nasal spray formulation into each nostril of a human subject. Preferably, the nasal spray formulation does not include a preservative.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention discloses an intranasal composition, preferably without preservatives, in a spray container in multiple doses or two doses or unit doses for treating pain associated with trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache.

Background Art

[0002] Nasal administration formulations without preservatives have revealed several interesting aspects. Nasal administration formulations intended for long-term use are usually preserved. However, it is now recognized that preservatives have an adverse effect on the ciliated tissue of the nasal cavity. The ciliary epithelium plays a decisive role in the function of the nose. The movement of the cilia serves to transport inhaled particles trapped in the nasal mucosa. Debris is directed towards the throat and then removed by swallowing. This clearing function prevents foreign matter from reaching the lungs. The effect of preservatives on the beating frequency of cilia can be explained as ciliostasis. In the case of nasal infections such as perennial rhinitis, the nasal mucus is highly contaminated, so it is important to remove the infected mucus as quickly as possible. In the case of severe allergies for treating infections, patients apply a preserved nasal spray three times a day for up to three months. However, preservatives act in the opposite way and delay the removal of mucus. The German health authority (BfArM) recently issued a risk statement regarding the widely used preservative benzalkonium chloride. The patient information leaflet should state that frequent administration of benzalkonium chloride irritates the nasal mucosa and that it is necessary to use alternative non-preserved products. The same is true for benzyl alcohol, which is commonly used as a preservative (see, for example, U.S. Patent No. 8,580,282). In the HSDB database of the National Library of Medicine, it is described that benzyl alcohol irritates the skin at levels above 3% 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 within two hours.

[0003] For nasal products that are not stored, single-dose and two-dose delivery systems that deliver one or two doses to the nostrils are common. Since these devices are disposable, there is no risk of contamination during use. Multiple-dose systems have different functional designs and patients need to use them daily for up to six months. In the case of non-stored contents, the drug delivery product will surely be contaminated during use.

[0004] Trigeminal neuralgia (TN) is defined by the International Association for the Study of Pain (IASP) as "an acute, usually unilateral, severe, brief, stabbing, recurrent pain attack 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 other than vascular compression of the trigeminal nerve is found. Symptomatic TN represents patients in whom a cause other than vascular compression, such as a tumor, arteriovenous malformation, or multiple sclerosis (MS), can be identified. According to research in Europe, trigeminal neuralgia is comparable to other neuropathic pain states and has been shown to cause significant interference with activities of daily living that can lead to suicide.

[0005] There is no specific treatment for trigeminal neuralgia. Treatment is strictly palliative and aims to relieve symptomatic pain, and the treatment goal is to reduce the pain to an acceptable level. Pharmacological treatments currently available for the symptomatic relief of TN include antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), antiepileptic drugs, and opioids. In this specific indication, the drug needs to act quickly and only locally, and systemic absorption needs to be minimized to avoid the systemic side effects associated with typical oral formulations of equivalent drug substances. The present invention of intranasal delivery of sodium channel local anesthetics provides rapid onset of pain relief and reduction of associated side effects. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0006] Object and Summary of the Invention An object of the present invention is to provide a preparation and a method for providing pain relief in humans and animals by administering an intranasal dose of a local anesthetic preparation free of preservatives for the treatment of trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache.

Means for Solving the Problems

[0007] In accordance with the foregoing and other objects, the present invention is directed in part to a nasal spray formulation of a topical sodium channel blocker for treating pain, comprising about 5% to about 30% w / v of a topical 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 has a viscosity of 0.8 to about 1.1 cps and is contained in a mechanical multiple-dose pump that sprays a unit dose of the nasal spray formulation having a wide plume and a small droplet size, and the unit dose is administered by operating the mechanical multiple-dose pump and spraying a volume of the nasal spray formulation into each nostril of a human subject. The present invention is further directed in part to a unit dose of a nasal spray formulation of a topical sodium channel blocker for treating pain, comprising about 5% to about 30% w / v of a topical sodium channel blocker, a buffering agent for providing a pH of about pH 4.5 to about pH 7 of 0.25% to about 5% w / v, and about 5 to about 99% w / v of a pharmaceutically acceptable carrier for nasal administration. Here, the nasal spray formulation has a viscosity of about 0.8 to about 1.1 cps and is contained in a mechanical multiple-dose spray pump device, and the unit dose is delivered as a wide plume defined by an average spray angle of about 50 degrees to about 95 degrees and a small droplet size 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, in a volume of about 0.04 ml to about 0.2 ml. 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 operating the mechanical multiple-dose pump provides a volume of about 40 μl to about 120 μl. In certain preferred embodiments, the mechanical multiple-dose pump provides a volume of about 100 μl (0.100 ml). When administered in unit dose into the nasal cavity, 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 local anesthetic 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 pharmaceutically acceptable carrier for nasal administration comprises water. In certain preferred embodiments, the nasal spray formulation provides a droplet size of about 5 to about 500 microns when sprayed. In certain preferred embodiments, the local anesthetic 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 preferred embodiments, the mechanical multiple-dose pump includes a spring valve located directly below the opening of the tip opening, and the mechanical multiple-dose pump is not allowed to move microorganisms from any surface or from the contacted liquid into the system, and / or the mechanical multiple-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 contain a preservative.

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

[0010] In certain preferred embodiments, the mechanical multiple-dose pump provides a small droplet size (μm) during operation, 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 multiple-dose pump preferably provides an average spray angle of about 50 to about 95 degrees. Preferably, the spray pattern of the multiple-dose pump spray has an average D of about 10 to about 45 mmmin , D of about 40 to about 70 mm max , providing an ellipticity of about 0.5 to about 2 mm. The ellipticity is calculated as the value obtained by dividing D max by D min . In certain embodiments, the spray pattern of the multiple-dose pump spray has an area percentage of about 12 to about 22 mm.

[0011] The present invention further relates to a method 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, the method comprising treating the pain by incorporating a nasal spray formulation containing a locally active sodium channel blocker, 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, and from about 5 to about 99% w / v of a pharmaceutically acceptable carrier for nasal administration, the nasal spray formulation having a viscosity of from about 0.8 to about 1.1 cps, being contained in a mechanical multiple-dose pump that sprays a unit dose of the nasal spray formulation having a wide plume and small droplet size upon actuation, the unit dose being therapeutically effective for 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 multiple-dose pump comprises (i) a spring-loaded valve located immediately below the opening of the tip opening to prevent the mechanical multiple-dose pump from transferring microorganisms from the surface or contacting liquid into the system; or (ii) a hydrophobic filter membrane having a pore size of less than 0.2 μm; or (iii) both (i) and (ii) above, and the nasal spray formulation does not contain 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 a particularly preferred embodiment, the locally active sodium channel blocker is lidocaine and the unit dose provides from about 5 mg to about 20 mg of lidocaine to be sprayed into the nasal cavity of a human subject. In certain preferred embodiments, the mechanical multiple-dose pump provides a volume of about 0.100 ml. In certain preferred embodiments, the unit dose provides a droplet size of from 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 about 4-hour intervals.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 local anesthetic sodium channel blocker, and any combination of the foregoing. In certain preferred embodiments, the spray pattern of the mechanical multiple-dose pump spray preferably has an average D of about 15 to about 45 mm. min , a D of about 40 to about 70 mm max , 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 with 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 pharmaceutically 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, operating a mechanical multiple-dose nasal spray pump device, and administering a nasal spray formulation by spraying 1 to 2 sprays into each nostril of a human subject, thereby providing an effective amount of a local anesthetic 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, and the second active agent is selected from the group consisting of epinephrine, a vasodilator, an anticonvulsant, a muscle relaxant, an analgesic that is not a local anesthetic sodium channel blocker, and any combination of the foregoing. 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 provides a volume of about 0.08 ml to about 0.12, and in certain embodiments about 0.10 ml. The nasal spray formulation is preferably administered by operating a mechanical multiple-dose pump and spraying about 1 to 2 sprays into each nostril of a human subject, for a total of about 4 sprays per application, thereby providing an effective dose of a local anesthetic sodium channel blocker. When the local anesthetic sodium channel blocker is lidocaine, the intranasal formulation can be administered at about 4-hour intervals.

[0012] In the method, in certain preferred embodiments, the mechanical multiple-dose pump is provided such that when in operation, the mechanical multiple-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 multiple-dose pump provides an average spray angle of about 50 to about 95 degrees. Preferably, the spray pattern of the mechanical multiple-dose pump spray has an average D min of about 15 to about 45 mm max and a D of about 40 to about 70 mm

[0013] In certain embodiments, the pharmaceutically acceptable carrier for nasal administration comprises or consists of water.

[0014] In certain preferred embodiments, the method further comprises positioning a mechanical multiple-dose pump such that when in operation, it provides a spray droplet size of about 5 to about 500 microns.

[0015] In certain preferred embodiments, the drug (e.g., a local anesthetic) constitutes 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 a preservative (optional) 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 the 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) included in the nasal spray formulation of the present invention.

[0017] All numbers representing amounts of ingredients, reaction conditions, etc. used in the specification and claims should be understood to be modified in all cases by the term "about". Accordingly, unless otherwise specified, the numerical parameters set forth in this specification and the appended claims are approximations that vary depending on the desired properties sought to be obtained by the present invention. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical parameter should be construed in light of the number of significant digits and the ordinary rounding approach.

[0018] When a numerical range is indicated herein, it always means including any cited number (fraction or integer) within the indicated range. The phrase "range between" a first indicia and a second indicia, and the phrase "range from" a first indicia "to" a second indicia (range of the first indicia to the second indicia) are used interchangeably herein and mean including the first and second indicia 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 "compound" or "at least one compound" includes plural compounds and mixtures thereof.

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

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

[0022] The term "comprising" as used herein is an inclusive term meant to mean containing, encompassing, covering or including the elements listed after the term, but not excluding other unrecited elements.

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

[0024] As used herein, the terms "treating" or "treatment" of a disease include preventing the disease from occurring (preventive treatment), suppressing the disease (delaying or preventing onset), providing reduction of symptoms or side effects of the disease (including palliative treatment), and reducing the disease (causing regression of the disease) in an animal that is susceptible to the disease but has not yet experienced or shown symptoms 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, drugs. The term "active agent" is further meant to include a single active agent present in a formulation, or a plurality (two or more) of active agents.

[0026] As used herein, the droplet size distribution can be characterized by the following measurement criteria: volume distribution (Dv10, Dv50, Dv90) and span and percentage (%) are less than 9 μm in accordance with the FDA CMC guidance for nasal sprays and inhalation solutions, suspensions, and spray drug products - chemistry, manufacturing, and controls document, July 2002. Dv10 means, for example, the diameter at which 10% of the total spray volume is composed of droplets of the same or smaller diameter. Dv50 means, for example, the diameter at which 50% of the total spray volume is composed of droplets of the same or smaller diameter. Dv90 means, for example, the diameter at which 90% of the total spray volume is composed of droplets of the same or smaller 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 minIt is defined as the shortest diameter measured on the resulting spray pattern image.

[0029] For the purposes of the present invention, the spray pattern can be characterized by one or more of the following measurement criteria: FDA guidance for industry: In accordance with the bioavailability and bioequivalence tests for nasal aerosols and nasal sprays for topical action, D max D min , ellipticity, and area%.

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

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

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

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

Brief Description of the Drawings

[0034]

Figure 1

[0035]

Figure 2

Modes for Carrying Out the Invention

[0036] In certain embodiments, the present invention is directed to a method of treating pain, comprising administering, via use of a (mechanical pump) metered spray device, a preservative-free intranasal composition in multiple doses or two doses or unit doses spray.

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

[0038] The present invention discloses a multiple dose or two dose or unit dose preservative-free intranasal composition in a 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 systemic pain, neuropathic pain (e.g., erythromelalgia, postherpetic neuralgia (PHN), fibromyalgia and / or complex regional pain syndrome (CRPS), etc.).

[0039] The liquid pharmaceutical composition of the present invention comprises a pharmaceutically acceptable liquid carrier, e.g., purified water, a pharmaceutically effective amount of a sodium channel blocker (e.g., lidocaine), and any buffer, e.g., citrate, for maintaining the pH at 3 to 8, preferably 3 to 6, and any complexing agent, e.g., citrate or EDTA, for inhibiting precipitation of the pharmaceutical substance from the aqueous medium.

[0040] Lidocaine (Xylocaine) was introduced as a local anesthetic in 1948. Local anesthetics act by preventing the generation and conduction of nerve impulses. Their main site of action is the cell membrane. They block conduction by reducing or preventing a large transient increase in the permeability of the excitatory membrane 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-dependent Na+ channels. As the anesthetic effect develops gradually in the nerve, the threshold of electrical excitability increases gradually, the rate of rise of the action potential decreases, impulse conduction slows down, and the safety factor of conduction decreases. Due to these factors, the possibility of propagation of the action potential decreases and nerve conduction fails. Bupivacaine, a longer-acting variant of lidocaine, is a 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 higher the frequency of 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 can access the binding site within 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 and stabilizes the inactivated state of the Na+ channel. Local anesthetics exhibit these properties to varying degrees depending on their pKa, lipid solubility, and molecular size.

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

[0043] In certain preferred embodiments of the present invention, a therapeutically effective amount of one or more pharmaceutically 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 formulation 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, butamben, 2-chloroprocaine, cyclomethycaine, ethyl aminobenzoate, eutypin, 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 a mixture thereof. The term "local anesthetic" also includes classes of drugs different from 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, thiopental, thiamylal), 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 recognized as having local anesthetic properties, such as the substituted piperidines and pyrrolidines described in U.S. Patent No. 4,302,465 (Aberg, et al.), and the aminoindane piperidine compounds described in U.S. Patent No. 6,413,987 (Aberg, et al.).Both of these patents are incorporated herein by reference. The term local anesthetic is also considered for the purposes of the present invention to include local anesthetic bases or pharmaceutically acceptable salts, polymorphs, complexes or prodrugs thereof. Many other examples of drugs and local anesthetics will be readily apparent to those skilled in the art and are considered to be included in the present disclosure and the appended claims.

[0044] The local anesthetic can be in the form of a salt, for example, hydrochloride, bromide, acetate, citrate, carbonate, sulfate or phosphate. In certain embodiments, the local anesthetic is in the form of the free base. The local anesthetic can be in the form of a salt, for example hydrochloride, bromide, acetate, citrate, carbonate or sulfate, or in the form of the free base. Many of the local anesthetics are usually used in the form of acid addition salts. This is to provide solubility in aqueous injection media. In certain embodiments of the present invention, it is desirable to use the local anesthetic in the free base form or with only a small amount of the acid addition salt of the local anesthetic present (the release may be enhanced by adding a small amount of the acid addition salt if necessary). The free base usually slows the initial release and avoids early "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 a unit dose is from about 1 mg to about 30 mg based on the unit dose of lidocaine. In other preferred embodiments, the dose is from about 5 mg to about 20 mg, preferably from 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 understand the methods for determining the equipotent doses of local anesthetics. The following maximum doses and durations of action of local anesthetics are generally recognized: 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, 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, a nasal spray was prepared by adding a drug, an optional buffer to a solvent while stirring the solution to ensure complete dissolution of the drug and excipient. The formulation was stored in a glass vial tightly sealed with a metered spray pump.

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

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

[0049] In certain preferred embodiments, the drug is supersaturated in the formulation. It is believed that the closer the drug in the formulation is to supersaturation, the more penetration is obtained, for example when the drug is administered by spraying into the nasal cavity.

[0050] In certain preferred embodiments, the active agent (drug) is a combination of a therapeutically effective amount of a local anesthetic (e.g., lidocaine) for use in the treatment of pain, ketamine, and / or amitriptyline. In certain embodiments, the active agent comprises 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) for use in the treatment of pain, meloxicam, and / or other muscle relaxants. In certain embodiments, the active agent comprises 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 combination of a therapeutically effective amount of a local anesthetic (e.g., lidocaine) for use in the treatment of pain, epinephrine, and / or a vasodilator. In certain embodiments, the active agent comprises a combination of lidocaine hydrochloride and 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 heart disease, and analogs thereof.

[0052] In certain preferred embodiments, the active agent (drug) is a combination of a therapeutically effective amount of a local anesthetic (e.g., lidocaine) for use in the treatment of pain, carbamazepine, and / or an anticonvulsant. 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, antiepileptic drugs, and combinations thereof.

[0053] The formulation of the present invention can also include two or more of the above components (drugs) or pharmaceutically acceptable salts, complexes or derivatives thereof.

[0054] Optional excipient In addition to the active agent (e.g., a local anesthetic), the nasal spray formulation may further include physiologically acceptable components such as sodium chloride, and similar substances conventionally used to achieve isotonicity with typical body fluids, a pH buffer for establishing a physiologically compatible pH range, and for enhancing the solubility of the anesthetic, vasodilator, e.g., epinephrine, preservative, stabilizer and antioxidant present.

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

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

[0057] Optional bacteriostatic or bactericidal concentration of antibacterial agents can be added to the formulations packaged in multi-dose containers, including phenol or cresol, mercury agents, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate esters, thimerosal, benzalkonium chloride, benzethonium chloride, boric acid, p-hydroxybenzoate, phenol, chlorinated phenol compounds, alcohols, quaternary compounds, mercury agents, mixtures thereof, etc. Optional tonicity agents include, but are not limited to, sodium chloride and dextrose as examples. Optional suspending and dispersing agents include sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinyl pyrrolidone. Optional emulsifying agents include polysorbate 80 (TWEEN® 80). Pharmaceutically acceptable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, or lactic acid as examples. In some embodiments of the present invention, especially when the active agent is in its base form (e.g., lidocaine base), a pharmaceutically acceptable buffer or acidifying agent is used to adjust the pH.

[0058] In certain other embodiments, the formulation can be made isotonic through the addition of tonicity agents conventionally used to achieve isotonicity with typical body fluids, pH buffers to establish a physiologically compatible pH range, e.g., but not limited to, any pharmaceutically acceptable sugar, salt, or any combination or mixture thereof, e.g., 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 present invention has the following composition (% w / w): Active agent 5 - 20% w / v Buffer 0.25 - 5% w / v Purified water 5 - 99% w / v Preservative (optional) 0.25 - 5 w / v Viscosity: 0.8 - 1.1 cps

[0060] The preparation 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-hydroxybenzoate, phenol, chlorinated phenol compounds, alcohols, quaternary compounds, mercury agents, mixtures thereof, etc.

[0061] Formulation without preservatives When using a multi-dose product that does not contain a preservative, there are two ways for microorganisms to enter the system: (1) through the pump opening; and (2) through the vent air that replaces the supplied liquid. In a preserved preparation (conventional system), the added preservative controls the growth of microorganisms and no additional measures are required to prevent the invasion of microorganisms through the opening or ventilation. If the preparation does not contain a preservative, the device must be able to keep microorganisms away from the system. The risk of infection is usually highest at the opening. This is because the opening can come into contact not only with infected body fluids but also with the skin and mucous membranes.

[0062] To prevent microbial contamination in the present invention, in certain preferred embodiments regarding the pump opening, a mechanical approach is included to minimize the interaction between the components of the device and the preparation. For example, in certain preferred embodiments, a spring valve is placed directly below the opening of the tip opening, which does not allow microorganisms to move from the surface or the contacted liquid into the system. Thus, the opening is "sealed" in a resting state. The tip seal keeps the system closed until the system is activated and reaches a defined pressure. Next, the preparation is extruded from the opening at a pressure higher than the pressure required to open the valve when the system opens. When the pressure drops at the end of the operation, the tip seal moves outward and closes the opening immediately. This prevents the backflow of contaminated pharmaceuticals and other liquids.

[0063] In additional or alternative embodiments, to prevent microbial contamination, microbial contamination of the formulation is avoided by aerating the air using a sterile filtration system. The aerating air of the pressure equalization system is forced through a sterile filter with a pore size of less than 0.2 μm. The filter membrane is usually hydrophobic and prevents liquid from leaking from the container through the aeration system.

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

[0065] Mechanical nebulizer 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 multiple-dose pump having an average spray volume, e.g., from about 40 μl to about 120 μl. Preferably, the multiple-dose pump sprays with a wide plume and a small droplet size. A useful representative multiple-dose pump is the Pfeiffer SAP-62602 multiple-dose pump (130 μl / actuation) (Pfeiffer, Princeton, NJ). For the purposes of the present invention, a "wide plume" means that the spray pump pattern has an average spray angle of preferably from about 50° to about 95°, more preferably from about 60° to about 90°, most preferably from about 70° to about 80°; and an average plume width (mm) of from about 20 to about 70 mm, more preferably from about 30 to about 60 mm, most preferably from about 42 to about 52 mm. The term "small droplet size" for the purposes of the present invention means a droplet size (μm) having an average Dv10 of from about 10 to about 30, an average Dv50 of from about 20 to about 60, and an average Dv90 of from about 80 to about 120. The spray pattern of the multiple-dose pump spray preferably provides an average D of from about 15 to about 45 mm min , a D of from about 40 to about 70 mm max , an ellipticity of from about 0.5 to about 2 mm, and a percentage of an area of from about 12 to about 22 mm.

[0066] In certain preferred embodiments of the present invention, a multiple-dose pump (metering device) having the features described in US Patent Publication No. 2007 / 026090A1, the disclosure of which is hereby incorporated by reference in its entirety, is used. For example, at least one metering device for a medium, comprising a pump unit operably connected to a medium reservoir for the purpose of discharging the medium, and a venting device assigned to the medium reservoir and / or the pump unit, having a venting 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 membrane is designed in particular as a stretched or perforated plastic film or sintered material, but also as a metal foil, and can vary within a wide range 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. If the number of channels or pores is large and the free cross-sectional area of each individual channel or pore is large, the effective cross-sectional area becomes large and a high diffusion rate becomes possible. That is, a large number of molecules can pass through the filter membrane even at a low pressure difference. In certain preferred embodiments, the effective surface area of the filter membrane is less than 1.4 mm 2 less, preferably less than 0.6 mm 2 less, particularly preferably less than 0.2 mm 2 less. In another embodiment, in order to obtain a reduced effective cross-sectional area, the average 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 the gas molecules that can pass through the filter membrane is reduced. In another embodiment, the filter membrane has less than 1 million pores per mm 2 , preferably less than 600,000 pores per mm 2 , particularly preferably less than 300,000 pores per mm 2 on average.

[0067] In certain preferred embodiments of the present invention, a multiple - dosing pump (metering device) having the features described in U.S. Patent No. 8,382,010, the disclosure of which is incorporated herein by reference in its entirety, is used. This U.S. patent describes a dosing device comprising manually operable pumping means, a pump chamber, and an injection valve configured as a slide valve, which is movable in a sealed manner by a dosing stroke within a dosing channel in a closed position, defining the dosing volume of the pump chamber, and the dosing channel opening into the injection area on the injection side. The device preferably further includes at least one gas - flow capillary, one end of which is open to the environment and the other end leads to a media reservoir, and a filter unit is provided at the end facing the media reservoir. Thereby, the media reservoir can be ventilated without causing contamination of the media by ambient air. In certain preferred embodiments, the multiple - dosing pump includes a manually operable pump device having a pump chamber and an injection valve constructed as a slide valve, the slide valve having a cylindrical dosing channel consisting of an upper and a lower part, the upper and lower parts being coaxially aligned with a pumping shaft, a lower wall surface having a circumferentially spaced flow profiling, and a piston having a sealing lip configured to slide along the length of the dosing channel in the direction of the pumping shaft, while successively sliding and engaging with the upper and lower wall surfaces of the dosing channel. The dosing channel on the injection side opens into a lower injection area remote from the upper part, and the injection area has a flow profiling configured to cause the opening of the slide valve upon movement of the sealing lip into the injection area. The sealing lip is in the closed position of the slide valve while sliding and engaging sealingly with the upper wall surface, and is configured to open in response to engagement of the sealing lip with the lower injection area caused by the flow profiling, whereby the media can flow through the sealing lip from the media reservoir through the flow profiling into the dosing channel and into the pump chamber. The sealing lip is sealingly movable along the pumping shaft over a dosing stroke within the dosing channel such that the slide valve defines the dosing volume of the pump chamber.Preferably, the flow profiling is formed by longitudinal grooves that are oriented in the longitudinal direction of the dosing stroke and extend parallel to the pumping axis over the axial length of the injection region, and the flow profiling is arranged in a circumferential direction of the injection region in a uniformly distributed manner with respect to each other. In certain preferred embodiments, the injection region and the dosing channel are provided on separate components. The components are preferably joined to each other in a coaxially engaged manner, and on the opposing circumferential surfaces, the components are profiled such that at least one gas flow capillary is formed between the front edges facing axially of the circumferential surfaces. Preferably, the gas flow capillary has a first end that opens to the environment outside the device, a second end that opens to the media reservoir, the second end faces the media reservoir, and a filter unit is provided.

[0068] Treatment The intranasal formulation of the present invention can be packaged in a multi-dose or two-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.

[0069] When the intranasal formulation contains a local anesthetic (e.g., lidocaine, bupivacaine, ropivacaine, mepivacaine, tetracaine alone and / or in combination), the mechanical nebulizer device preferably delivers a volume of, for example, about 0.04 ml to about 0.12 ml, or about 0.10 ml. In such an example, the formulation can be administered intranasally by spraying 1 to 2 times into each nostril as a total of about 4 sprays per application (to provide an effective amount). When the drug is lidocaine, the intranasal formulation is administered, for example, at approximately 4-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 local active sodium channel blockers, and combinations of any of the foregoing. Preferably, the second active agent is incorporated into a nasal spray formulation. However, the second active agent can be administered, for example, separately from, simultaneously with, or sequentially to a local anesthetic.

Examples

[0071] Detailed description of preferred embodiments The following examples according to the present invention should not be construed as limiting the present invention in any way and are merely samples of various formulations described herein.

[0072] Examples 1-3 A lidocaine preservative-free intranasal formulation is prepared using the components 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 any other optional excipients are added with stirring and mixed for 30 minutes until a clear solution is formed. The clear solution is filtered using a sterile 0.2 micron pore size filter, the solution is aseptically filled into a glass bottle, and the mechanical pump for the metered dose is crimped firmly.

[0074] Examples 4-5 A lidocaine preservative-free intranasal formulation is prepared using the components 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. The clear solution is filtered using a sterile 0.2 micron pore size filter, the solution is aseptically filled into a glass bottle, and the mechanical pump for metered dosing is firmly crimped. The droplet size distribution of the intranasal spray of Example 5 is shown in Table 3.

Table 3

[0076] Examples 6 - 8 An intranasal formulation without lidocaine preservative in combination with other drugs is prepared using the ingredients shown in Table 4 for Examples 6 - 8.

Table 4

[0077] The formulation is prepared as follows: Citric acid monohydrate is added to purified water with stirring and mixed until a clear solution is observed. With stirring, lidocaine base or salt, co - administered drug, and other optional excipients are added and mixed for 30 minutes until a clear solution is formed. The clear solution is filtered using a sterile 0.2 micron pore size filter, the solution is aseptically filled into a glass bottle, and the mechanical pump for metered dosing is firmly crimped.

[0078] Example 9 (In - vivo test) To evaluate the drug release from lidocaine nasal sprays prepared according to Examples 4 and 5, in vivo tests were performed in healthy rabbits. The pharmacokinetics of two different formulations (Examples 4 and 5) were evaluated, a single-dose test at 10 mg of lidocaine per spray (nasal spray formulation), 0.10 ml per spray, to access local anesthetic activity. A total of 18 New Zealand white rabbits (both male and female) were used. These 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). Each group had 6 rabbits (3 males and 3 females).

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

[0080] The composition was sprayed using a Pfeiffer SAP-62602 multiple-dose pump (130 μL / actuation) (Pfeiffer, Princeton, NJ).

[0081] The plasma concentration-time profiles of lidocaine after intranasal administration (Examples 4 and 5) and placebo administration route, individual and mean pharmacokinetic parameters are shown in Table 5. The mean pharmacokinetic (plasma concentration-time) profile is shown in Figure 1.

[0082] The lidocaine plasma concentration was found to be below the LLOQ of the placebo group #3 and was not considered in the estimation of PK parameters.

[0083] Group 1 (Example 5): The mean Cmax was found to be 724 ng / mL at a median Tmax of 0.25 hours. The 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 at a median Tmax of 0.25 hours. The AUC 0‐t and AUC 0‐infinity were found to be 979 and 1010 ng*hr / m, respectively. The mean disappearance half-life was found to be 0.928 hours. The clearance and volume of distribution were 345 ml / min and 27 L, respectively.

Table 5

[0085] Formalin irritation 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 Formulation Examples 5, 4, and placebo, respectively. The mean amplitude was found to be 4.65, 8.96, and 13.64 seconds for the test formulations of Example 5 (identified as Test Formulation 1 in Figure 2), Example 4 (identified as Test Formulation 2 in Figure 2), and placebo (identified as Test Formulation 3 in Figure 2), respectively. The data were statistically analyzed using an unpaired t-test for comparison of Test Formulations Examples 4 and 5 with the placebo formulation. The amplitude of the rubbing motion is shown in Figure 2. A significant decrease in the formalin-induced pain / stimulation score was observed for both Test Formulations Examples 4 and 5 compared to 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 Harmonization of Pharmaceutical Regulations (ICH) is a project that brings together regulatory authorities and pharmaceutical industry experts from Europe, Japan, and the United States.

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

[0089] Conclusion The examples provided above are not meant to be exclusive. Many other variations of the present invention will be apparent to those skilled in the art and are considered to be within the scope of the appended claims.

[0090] The active agent can be incorporated into the nasal formulation in therapeutically equivalent amounts. The actual dosage (relative potency) of the active agent can be determined based on the comparative dosage to the therapeutically effective dosage of the active agent described herein.

Claims

1. A unit dose of a nasal spray formulation of a topical sodium channel blocker for treating pain, comprising about 5% to about 30% w / v of a topical sodium channel blocker, a buffer for providing a pH of about pH 4.5 to about pH 7 at about 0.25% to about 5% w / v, and about 5 to about 99% w / v of a pharmaceutically acceptable carrier for nasal administration, wherein the nasal spray formulation has a viscosity of about 0.8 to about 1.1 cps, is contained in a mechanical multiple-dose spray pump device, the unit dose is delivered as a wide plume defined by an average spray angle of about 50 to about 95 degrees and as 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 in a volume of about 0.04 ml to about 0.2 ml, and 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.

2. The unit dose of the nasal spray formulation according to claim 1, wherein the mechanical multiple-dose spray pump device includes a spring valve located directly below the opening of the tip opening, the mechanical multiple-dose spray pump device prevents microorganisms from moving into the system from the surface or the contacted liquid, and the mechanical multiple-dose spray pump device includes a sterilization filtration system including a hydrophobic filter membrane with a pore size of less than 0.2 μm, and the nasal spray formulation does not contain a preservative.

3. The unit dose of the nasal spray formulation according to claim 1 or 2, wherein the mechanical multiple-dose pump provides a volume of about 0.100 ml.

4. The unit dose of the nasal spray formulation according to claim 1 or 2, wherein the topical sodium channel blocker is lidocaine and the intranasal formulation is administered at about 4-hour intervals.

5. The unit dose of the nasal spray formulation according to claim 1, further comprising a second drug selected from the group consisting of an anticonvulsant, a vasodilator, a muscle relaxant, an analgesic that is not a topical sodium channel blocker, and any combination of the foregoing.

6. The unit dose of the nasal spray formulation according to claim 1 or 2, providing a droplet size of about 5 to about 500 microns.

7. The spray pattern of the mechanical multiple-dose pump spray preferably provides an average D of about 15 to about 45 mm ｍｉｎ , a D of about 40 to about 70 mm ｍａｘ , and an ellipticity of about 0.5 to about 2 mm, for a unit dose of the nasal spray formulation according to claim 1 or 2.

8. The unit dose of the nasal spray preparation according to claim 1 or 2, wherein the wide plume is defined by an average spray angle of about 60 degrees to about 90 degrees.

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

10. The unit dose of the nasal spray preparation according to claim 9, wherein the average plume width is about 30 to about 60 mm.

11. The unit dose of the nasal spray preparation according to claim 1, 2 or 5, wherein the local anesthetic sodium channel blocker is lidocaine, and the unit dose of the nasal spray preparation provides about 5 mg to about 20 mg of lidocaine.

12. The unit dose of the nasal spray preparation according to claim 1 or 5, wherein the locally acting sodium channel blocker is selected from the group consisting of lidocaine, mepivacaine, bupivacaine, ropivacaine, chloroprocaine, procaine, tetracaine, and any combination thereof.

13. The unit dose of the nasal spray preparation according to claim 1, wherein the pharmaceutically acceptable carrier for nasal administration contains water.

14. Use of the unit dose of the nasal spray preparation according to claims 1, 2 and 5 in the treatment of a human patient having a condition selected from trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache.

15. Use of the unit dose of the nasal spray preparation according to claim 1 in the treatment of a human patient having a condition selected from trigeminal neuralgia, facial neuropathic pain, facial cancer-induced neuropathic pain, migraine, and cluster headache, comprising operating a mechanical multiple-dose nasal spray pump device and spraying 1 to 2 sprays into each nostril of a human subject to provide an effective amount of a local anesthetic sodium channel blocker, thereby administering the nasal spray preparation intranasally.

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