Rapidly degrading formulations for reversing intentional incapacitation

Abstract

Provided herein are formulations and methods for reversing incapacitation from intentional poisoning, and can include administering to a subject one or more fast-degrading unit dosage forms or nasal sprays, wherein the fast-degrading unit dosage forms and the nasal sprays comprise flumazenil. The unit dosage forms can be selected from the group consisting of a dissolving lozenge, a lollipop, a sublingual film, and a buccal tablet, and can comprise about 0.2 mg to about 2 mg of flumazenil, and the sublingual film can degrade in the mouth in about 3 to about 6 minutes.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 592,568, filed October 23, 2023, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0003] Drug-assisted sexual assault (often also known as date rape) refers to sexual assault in which the victim is subjected to one or more drugs, and it is a significant and widespread social problem. Drug-assisted sexual assault can involve voluntary (“opportunistic” drug-assisted sexual assault) or involuntary (“active” drug-assisted sexual assault) ingestion of drugs. Active drug-assisted sexual assault involves the perpetrator administering drugs or “poisoning” the target victim, which may incapacitate the victim by rendering them unconscious or less able to resist the attacker. This poisoning can be done by mixing the target victim’s drink and / or food, so that the victim ingests the drug unknowingly. The drugs used for this purpose (incapacitating or “date rape” drugs) are diverse, but mainly belong to the family of drugs that are γ-aminobutyric acid (GABA) receptor agonists. GABA receptors mediate inhibitory neural pathways, thereby suppressing consciousness and inducing sleep.

[0004] GABA receptor agonists (usually belonging to the benzodiazepine (BZD) class) are commonly used by criminals as incapacitating drugs. The infamous incapacitating drug Rohypnol (flunitrazepam, also commonly known as "roofies") is a BZD GABA agonist (particularly GABAA). Similarly, at sufficiently high doses, many other benzodiazepines exhibit the same or similar effects as intoxication, loss of motor coordination, loss of consciousness, and even retrograde and anterograde amnesia, in which victims cannot even remember the immediate events before or after the drugging. This amnesia effect is why criminals and predators often use these drugs, as the inability of victims to clearly recall events in the short period before and after drugging makes it difficult for them to provide sufficient information to law enforcement for conviction. In addition to drugs that strictly belong to the benzodiazepine class (which includes midazolam, triazolam, and diazepam), gamma-hydroxybutyric acid (also known as GHB) and “Z-drugs” (which include zolpidem, zaleplon, and zopiclone) also act on GABA receptors and are used by criminals for similar purposes.

[0005] Inappropriate doses of these incapacitating drugs are known to prevent victims from experiencing sensory impulses or responses after ingestion. For example, when ingested without any medical supervision or prescription, Rohypnol can cause adverse effects such as drowsiness, impaired motor skills, impaired judgment, decreased inhibition, dizziness, and confusion. GHB can produce toxic and amnesic effects. Furthermore, a combination of two chemical drugs in a beverage can act as a partial anesthetic, leading to partial or complete amnesia. In most cases, these drugs may be mixed with alcoholic beverages to have a greater effect on the victim.

[0006] Adding these chemicals to beverages can produce the aforementioned harmful effects on victims who may become targets of sexual assault. Furthermore, the harmful effects of these chemicals can begin 15 to 20 minutes after ingestion, providing victims with a brief window of time before they suffer physical or psychological damage from the effects of the incapacitating drugs. These effects become more severe when the chemicals are administered in large doses. In addition, large doses of these chemicals can cause permanent psychological harm to victims, and in some cases, overdose can lead to immediate death.

[0007] Many existing solutions to this problem focus on rapidly testing for the presence of incapacitating drugs in beverages or food to be ingested. For example, U.S. Patent Publication No. 2011 / 0195507 provides a test stick for immersing in beverages to test for the presence of flunitrazepam (also known as Rohypnol). On the one hand, this information can prevent potential victims from ingesting beverages containing incapacitating drugs. However, if the victim has already ingested the drugged beverage or food, and the beverage or food is only tested after poisoning has occurred, this delay means that the victim has only a few minutes to remain conscious and thus escape the perpetrator or take self-rescue actions, because the drug needs to be absorbed systemically after oral administration before it can act on the brain.

[0008] When a victim unknowingly ingests a dose exceeding the threshold for this GABA agonist, it can lead to a rapid and progressive loss of motor control, loss of consciousness, dissociation, and anterograde amnesia. Following such an ingestion, the victim, experiencing these effects due to the ingestion of the incapacitating drug, becomes vulnerable and unable to resist the perpetrator's attacks (sexual assault or other forms of abuse). Therefore, there is an urgent need to provide targeted individuals with available proactive interventions as a countermeasure against such attacks. For example, there is a need for a reversal agent for incapacitating drugs that can be administered within a 15- to 30-minute therapeutic window. This article provides compositions, formulations, and methods that meet this need. Summary of the Invention

[0009] Some embodiments of this disclosure provide a method for reversing attempted poisoning incapacitation, comprising administering a rapidly degrading unit dosage form or nasal spray of flumazenil to a subject who has experienced a poisoning event. In some embodiments, each unit dosage form of a multi-dose flumazenil formulation contains an administered dose of flumazenil of 0.18 mg to approximately 0.3 mg, wherein the total dose administered within approximately 10 to 40 minutes after the subject becomes aware that a poisoning event has occurred is up to 5 unit doses.

[0010] In some embodiments, the poisoning event includes administration of an incapacitating drug to the subject. In some embodiments, 1 to 5 unit doses are administered within 40 minutes of the subject experiencing the poisoning event. In some embodiments, the incapacitating drug comprises a GABA agonist. In some embodiments, the GABA agonist is selected from the group consisting of: flunitrazepam, midazolam, triazolam, diazepam, γ-hydroxybutyric acid, zolpidem, zaleplon, and zopiclone. In some embodiments, the unit dose also comprises one or more pharmaceutically acceptable excipients. In some embodiments, the unit dose is selected from the group consisting of: tablets, lollipops, sublingual films, and lozenges. In some embodiments, each unit dose contains about 0.8 mg to about 1.0 mg of flumazenil, and wherein the unit dose is a sublingual film that degrades in the mouth within 3-6 minutes. In some embodiments, the sublingual film has a concentration of about 75-110 μg / cm³. 2 A diffusion flux of approximately 30-65 μg / cm³. In some embodiments, the sublingual film formulation has a diffusion flux of approximately 30-65 μg / cm³. 2 The diffusion flux is approximately 10-30 μg / cm³. In some embodiments, the sublingual film comprises about 0.9 mg of flumazenil and one or more pharmaceutically acceptable excipients, and wherein the sublingual film has a diffusion flux of approximately 10-30 μg / cm³. 2 diffusion flux per minute.

[0011] Some embodiments of this disclosure further provide a rapidly dissolving formulation comprising about 0.2 mg to about 2 mg of flumazenil, said formulation being a tablet, lollipop, sublingual film, or lozenge, and said formulation degrading in the mouth within about 3-6 minutes. In some embodiments, the formulation also comprises one or more pharmaceutically acceptable excipients.

[0012] Some embodiments of this disclosure further provide a sublingual film comprising about 0.2 mg to about 2 mg of flumazenil, wherein the sublingual film degrades in the mouth within about 3-6 minutes. In some embodiments, the sublingual film also comprises one or more pharmaceutically acceptable excipients.

[0013] Some embodiments of this disclosure further provide a sublingual film comprising about 0.18 mg to about 0.3 mg of flumazenil, wherein the sublingual film degrades in the mouth within about 3-6 minutes. In some embodiments, the sublingual film also comprises one or more pharmaceutically acceptable excipients. In some embodiments, the sublingual film has a concentration of about 75-110 μg / cm³. 2 A diffusion flux of approximately 30-65 μg / cm³. In some embodiments, the sublingual film formulation has a diffusion flux of approximately 30-65 μg / cm³. 2 The diffusion flux is approximately 10-30 μg / min. In some embodiments, the sublingual film contains 0.2 mg of flumazenil and has a diffusion flux of approximately 10-30 μg / cm³. 2 diffusion flux per minute.

[0014] Some embodiments of this disclosure further provide a sublingual film containing about 0.8 to about 1 mg of flumazenil, wherein the sublingual film degrades in the mouth within about 3-6 minutes. In some embodiments, the sublingual film also contains one or more pharmaceutically acceptable excipients. In some embodiments, the sublingual film has a concentration of about 75-110 μg / cm³. 2 A diffusion flux of approximately 30-65 μg / cm³. In some embodiments, the sublingual film formulation has a diffusion flux of approximately 30-65 μg / cm³. 2 The diffusion flux is approximately 10-30 μg / min. In some embodiments, the sublingual film contains 0.9 mg of flumazenil and has a diffusion flux of approximately 10-30 μg / cm³. 2 diffusion flux per minute. Detailed Implementation

[0015] This disclosure provides a broad-spectrum antidote for such deliberate, incapacitating drug administration, which can be used as a countermeasure against various potential GABA agonist poisonings. In many cases, when a potential victim unknowingly ingests a GABA agonist, the objective and subjective effects of poisoning gradually intensify. The effect is enhanced during the time required for the drug to be absorbed into the systemic circulation via the stomach and gastrointestinal tract. Over time, the ingested drug reaches higher plasma and brain concentrations. For example, oral midazolam (a fast-acting BZD drug) has an onset of action approximately 15-20 minutes after oral ingestion, with an average peak brain effect at 30-60 minutes.

[0016] Therefore, the effect of "incapacitating drugs" on a victim's complete incapacity is not always immediate. Thus, there exists a treatment window or time leeway (potentially a few minutes to half an hour, depending on the drug dosage and the presence of other synergistic GABA-acting molecules, including alcohol) to intervene with a fast-acting antidote to counteract the effects of the GABA agonist. Specifically, there is a time interval between when the victim becomes aware of suspected poisoning and when they become completely incapacitated. When GABA levels reach sufficiently high plasma and brain levels, the victim typically forgets this window of consciousness due to the amnesic effect of GABA drugs, without antidote intervention.

[0017] Another complicating factor negatively impacting a victim's ability to effectively resist "poisoning" is that the victim may doubt and be uncertain whether they have actually been "poisoned." A common occasion for smuggling beverages is a social setting where alcohol is also consumed. The victim may be unsure whether the gradual loss of mental capacity is a result of alcohol alone or an attack using a GABA agonist. Significant negative social pressure may exist, causing hesitation to alert others for fear of false accusations or embarrassment. This hesitation unfortunately allows more critical time to slip away, as the GABA agonist exerts a greater effect to incapacitate the targeted victim.

[0018] When victims realize they have been poisoned, their physical ability to escape the situation may be diminished as they become partially incapacitated. In cases where GABA agonists are secretly administered to victims who have already ingested alcohol, the effects of the GABA agent are amplified due to the synergistic effect of alcohol and the GABA agonist, as alcohol also stimulates GABA receptors at different binding sites.

[0019] Therefore, there is an urgent need for an emergency self-administered antidote that can rapidly counteract attempts by GABA agonists to incapacitate individuals using GABA agonists, preferably one that is available without a prescription (also known as an over-the-counter drug). This disclosure provides a dosage form of a GABA antagonist in a safe formulation that can counteract or antagonize the effects of orally administered GABA agonists by reaching the brain more quickly within the therapeutic time window.

[0020] In some implementations, the GABA antagonist is flumazenil. Flumazenil is an imidazobenzodiazepine derivative and a potent competitive antagonist of benzodiazepines and "Z-drugs" that acts on the central nervous system, reversing the pharmacological effects of benzodiazepines and "Z-drugs." Similarly, flumazenil also partially reverses alcohol-induced neurological effects. Flumazenil competitively inhibits activity at the benzodiazepine recognition site on the GABA / benzodiazepine receptor complex.

[0021] In some embodiments, the GABA antagonist is selected from the group consisting of: bicuculline, picotoxin (picrotin / picrotoxinin), gabazine, sepranolone, salicylidene salicylhydrazide (SCS), and bilobalide. In some embodiments, the GABA antagonist is bicuculline.

[0022] Flumazenil

[0023] Flumazenil is currently marketed only as a prescription drug in IV formulations. It is used in hospital settings to reverse benzodiazepine induction of anesthesia or to reverse benzodiazepine overdose cases seen in the emergency department. Flumazenil is not practical as an oral medication due to its extremely low oral availability. This is because of the first-pass effect, which causes flumazenil to be metabolized in the liver upon oral ingestion. To address this issue, this article provides dosage forms that are easier to administer by bypassing first-pass metabolism. In some embodiments, dosage forms are selected from the group consisting of: rapidly dissolving tablets, oral dissolving films / strips (e.g., held in place by the tongue), dissolving sublingual films or strips, and nasal sprays. Small molecule drugs delivered via these routes bypass the “first-pass” hepatic metabolism—allowing much higher doses to be rapidly delivered to the brain to reverse the effects of GABA agonists.

[0024] Not bound by any particular theory or mechanism, another key advantage of oral or sublingual formulations is that they are expected to reach peak plasma levels more quickly and arrive in the brain before or before an orally administered GABA agonist (a benzodiazepine). For example, in dentistry, triazolam typically reaches peak effect within 20 to 30 minutes sublingually, compared to 30 to 45 minutes for oral administration. Antidotes need to reach their receptor targets as rapidly as possible to counteract toxins that may have already reached concentrations sufficient to cause symptomatic effects.

[0025] The need for broad availability

[0026] In practice, individuals will carry single or multiple doses of the antidote (e.g., as a sublingual strip, oral lozenge, or nasal spray) or keep it within reach when in a risky environment where they may have been poisoned by GABA-like drugs. If an individual experiences neurological symptoms consistent with a potential poisoning event and before losing consciousness, the antidote can be rapidly administered, quickly reversing the effects of the GABA agonist to aid in escaping the dangerous situation.

[0027] In some implementations, the target individual will receive more than one single dose of this sublingual or oral flumazenil because the duration of effect of benzodiazepines (BZDs) or Z-drugs may exceed that of flumazenil (half-life < 1 hour). For example, many benzodiazepines have longer half-lives than flumazenil. Therefore, in the event of a poisoning attack, repeated doses of flumazenil may be necessary to prevent GABA agonist effects once the effects of the initial dose have worn off.

[0028] Ideally, the target individual should have a sufficient dose of flumazenil to counteract the effects of poisoning until safe and appropriate medical care is obtained.

[0029] Sublingual preparations

[0030] For sublingual administration, flumazenil films or tablets can be placed under the tongue. Unbound by any particular theory or mechanism, dissolved active flumazenil can directly enter the bloodstream / systemic circulation via the ventral surface of the tongue and the floor of the mouth. The reticular veins are located beneath the oral mucosa. Flumazenil is rapidly absorbed and transported via the facial vein, internal jugular vein, and brachiocephalic vein, and discharged into the systemic circulation. The sublingual route generally produces a faster onset of action and an improved AUC (area under the curve) than oral intake because flumazenil is absorbed through sublingual vessels and bypasses the first-pass metabolism in the liver. Unbound by any particular theory or mechanism, the primary route of absorption of flumazenil into the oral mucosa is likely via passive diffusion into the lipid membrane. For sublingual formulations, a small amount of saliva is usually sufficient for disintegration in the mouth. Absorption of flumazenil via the sublingual route is 3 to 10 times faster than via the oral route. Peak blood levels are reached within 10 to 15 minutes for most sublingually administered products, which is typically much faster than oral intake of these same drugs. Sublingual absorption is effective. The percentage of absorption per dose is typically higher than that achieved through oral intake.

[0031] In some embodiments, this disclosure provides a sublingual film formulation of flumazenil comprising about 0.2 mg to about 2 mg or about 0.2 mg to about 1 mg of flumazenil and one or more pharmaceutically acceptable excipients, wherein the diffusion flux is about 75-110 μg / cm / min. The sublingual film formulation of flumazenil is in the form of a unit dosage form comprising about 0.2 mg to about 2 mg or about 0.2 mg to about 1 mg of flumazenil and one or more pharmaceutically acceptable excipients, wherein the diffusion flux is about 30-65 μg / cm / min. 2 / min. In some embodiments, the sublingual film formulation of flumazenil comprises about 1 mg of flumazenil and one or more pharmaceutically acceptable excipients, wherein the diffusion flux is about 10-30 μg / cm. 2 / min.

[0032] In other embodiments, this disclosure provides a sublingual film formulation of flumazenil comprising flumazenil or a pharmaceutically acceptable salt thereof as the active ingredient, and a water-soluble polymer component. The sublingual film formulation may also optionally comprise other pharmaceutically acceptable excipients selected from: mucosal adhesives, plasticizers, surfactants / nonionic solubilizers, flavoring agents, sweeteners, and coloring agents. The "water-soluble polymer component" comprises approximately 5% to 75% w / w of the total weight of the flumazenil sublingual film formulation, approximately 35% to 75% w / w of the total weight of the flumazenil sublingual film formulation, or approximately 40% to 70% w / w of the total weight of the sublingual film formulation.

[0033] In other embodiments, the water-soluble polymer component includes polyethylene oxide, hydrophilic cellulose polymer (HPMC), and maltodextrin. In another embodiment, polyethylene oxide is present in the sublingual film at about 0% to 20% by weight, about 1% to 15% by weight, or about 10% to 15% by weight of the water-soluble polymer component. In another embodiment, hydroxypropyl methylcellulose is present in the sublingual film at about 30% to 90% by weight, about 40% to 90% by weight, or about 70% to 85% by weight of the water-soluble polymer component. In other embodiments, maltodextrin present in the sublingual film accounts for about 0% to 60% by weight, about 1% to 30% by weight, or about 5% to 15% by weight of the water-soluble polymer component.

[0034] Some embodiments of this disclosure provide a sublingual film formulation of flumazenil comprising flumazenil or a pharmaceutically acceptable salt thereof as the active ingredient and one or more pharmaceutically acceptable excipients, wherein the sublingual film formulation is prepared at a concentration of about 50-600 μg / αη.2 The diffusion flux delivers a dose of flumazenil over five minutes via a biological mucosa equivalent to the human oral mucosa. In some embodiments, the sublingual drug delivery of flumazenil delivers the target flux at a dose as low as approximately 2 mg / unit.

[0035] "Water-soluble polymer" can be a partially or primarily water-soluble polymer, a water-swellable polymer, or a combination of water-soluble and water-swellable polymers. The polymer can include cellulose or cellulose derivatives. Suitable examples of water-soluble polymers include, but are not limited to, polyethylene oxide, short-stem polysaccharides, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, water-swellable polysaccharides (such as starch), starch derivatives (such as polymers of dextrose, like maltodextrin), carrageenan, xanthan gum, locust bean gum, gum arabic, chitosan, alginate, hyaluronic acid, pectin, and combinations thereof. In some embodiments, the water-soluble polymer is a cellulose polymer, maltodextrin, polyethylene oxide, and combinations thereof. The cellulose polymer used in combination with polyethylene oxide and maltodextrin may be selected from the group consisting of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC). The combination of polyethylene oxide polymers with hydrophilic cellulose polymers and maltodextrin achieves a membrane with good adhesion, flexibility, and strength.

[0036] The drug may contain a "water-soluble polymer component" in an amount ranging from about 5% to 75% w / w of the total weight of the flumazenil sublingual film, about 35% to 75% w / w of the total weight of the flumazenil sublingual film, or about 40% to 70% w / w of the total weight of the drug sublingual film.

[0037] When present in a sublingual film, it may contain polyethylene oxide in an amount ranging from about 0% to 20% by weight of the water-soluble polymer component, about 1% to 15% by weight of the water-soluble polymer component, or about 10% to 15% by weight of the water-soluble polymer component.

[0038] Plasticizers can be incorporated to impart flexibility, enhance elasticity, and reduce brittleness. In some embodiments, plasticizers include triacetine, citrate derivatives (such as triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, trioctyl citrate, acetyl trioctyl citrate, trihexyl citrate, etc.), dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol, or combinations thereof. Plasticizers can be contained in amounts ranging from about 0% to 20% w / w of the total sublingual film, about 2% to 15% w / w of the total sublingual film, or about 3% to 12% w / w of the total sublingual film.

[0039] Mucosal adhesive polymers for adhesion to mucous membranes may be added, wherein the mucosal adhesive polymers are selected from the group consisting of: chitosan, hyaluronic acid salts, alginate, gelatin, collagen, poly(acrylic acid), poly(methacrylic acid), poly(L-lysine), poly(ethylene imine), poly(ethylene oxide), poly(2-hydroxyethyl methacrylate), and their salts or copolymers.

[0040] In some embodiments, the sublingual medicament contains at least one flavoring agent selected from natural and synthetic flavoring liquids. Exemplary lists of such agents include volatile oils, synthetic flavoring oils, flavoring agents, oils, liquids, oleoresins, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. A non-limiting representative list of examples includes peppermint oil, cocoa butter, and citrus oils (such as lemon, orange, grape, lime, and grapefruit), as well as fruit flavorings, including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruit flavoring agents.

[0041] In some embodiments, the sublingual film formulation incorporates at least one sweetener selected from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts, such as sodium salts; dipeptide sweeteners, such as aspartame; dihydrochalcone compounds, glycyrrhizin; stevia (stevioside); chlorinated derivatives of sucrose, such as sucralose; sugar alcohols, such as sorbitol, mannitol, xylitol, etc. Hydrogenated starch hydrolysates and synthetic sweeteners such as 3,6-dihydro-6-methyl-111,2,3-oxathiazin-4-one-2,2-dioxide, particularly its potassium salt (acesulfame-K) and its sodium and calcium salts, are also contemplated.

[0042] In some embodiments, the sublingual film formulation incorporates at least one diluent selected from the group consisting of mannitol, microcrystalline cellulose (MCC), lactose, and combinations thereof. In some embodiments, the diluent is mannitol. In some embodiments, the sublingual film formulation incorporates at least one surfactant / nonionic solubilizer selected from the group consisting of poloxamer, polyoxyethylene hydrogenated castor oil, glyceryl-based polyethylene glycol oxystearate, fatty acid glyceryl-based polyglycerol ester, polyglycerol ester, and combinations thereof. A colorant (e.g., a dye) may be added. Dyes suitable for pharmaceutical compositions may include, for example, natural dyes such as annatto extract, anthocyanins, β-carotene, βAPO8, carotene aldehyde, blackcurrant, burnt sugar, canthaxanthin, caramel, and carbomer. (medicinals), carmine, carmine blue, carmine acid, carrot, chlorophyll, chlorophyllin, cochineal extract, copper-chlorophyll, copper-chlorophyllin, curcumin, curcumin / CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, capsicum, riboflavin, titanium dioxide, turmeric, natural pigments, chokeberry / red berry, beet juice pigment, capsicum extract, capsicum oleoresin; or artificial dyes such as Allura Red, Brilliant Blue FCF, amaranth, carmoisine, fast red E, erythrosine, green S, patent blue V, ponceau 4R, quinoline yellow, red 2G, sunset yellow, FD&C yellow, and tartrazine.

[0043] In some embodiments, the sublingual film may have the composition of any of the exemplary formulations provided in Tables 1.1, 2.1, or 2.2. In some embodiments, the sublingual film may have the diffusion flux as provided in Table 1.2.

[0044] In some implementations, the tablets may have the composition of any of the exemplary formulations provided in Table 3.1 or 3.2.

[0045] Other formulations

[0046] In some embodiments, the rapidly degradable formulations of this disclosure may be in the form of lollipops, nasal sprays, or lozenges. Such formulations may contain about 0.2 mg to about 2 mg or about 0.2 mg to about 1 mg of flumazenil and one or more pharmaceutically acceptable excipients, with a diffusion flux of about 75-110 μg / cm / min. In some embodiments, the formulation contains about 0.2 mg to about 2 mg or about 0.2 mg to about 1 mg of flumazenil and one or more pharmaceutically acceptable excipients, with a diffusion flux of about 30-65 μg / cm / min. 2 / min. In some embodiments, the formulation comprises about 1 mg of flumazenil and one or more pharmaceutically acceptable excipients, wherein the diffusion flux is about 10-30 μg / cm³. 2 / min.

[0047] In other embodiments, this disclosure provides rapidly degradable formulations comprising flumazenil or a pharmaceutically acceptable salt thereof as an active ingredient, and a water-soluble polymer component. The rapidly degradable formulations may also optionally comprise other pharmaceutically acceptable excipients selected from: mucosal adhesives, plasticizers, surfactants / nonionic solubilizers, flavoring agents, sweeteners, and coloring agents. The “water-soluble polymer component” constitutes approximately 5% to 75% w / w, approximately 35% to 75% w / w, or approximately 40% to 70% w / w of the total weight of the formulation.

[0048] In other embodiments, the water-soluble polymer component includes polyethylene oxide, hydrophilic cellulose polymer (HPMC), and maltodextrin. In other embodiments, polyethylene oxide is present in the formulation at about 0% to 20% by weight, about 1% to 15% by weight, or about 10% to 15% by weight of the water-soluble polymer component. In further embodiments, hydroxypropyl methylcellulose is present in the formulation at about 30% to 90% by weight, about 40% to 90% by weight, or about 70% to 85% by weight of the water-soluble polymer component. In other embodiments, the amount of maltodextrin present in the formulation is about 0% to 60% by weight, about 1% to 30% by weight, or about 5% to 15% by weight of the water-soluble polymer component.

[0049] Some embodiments of this disclosure provide a formulation comprising flumazenil or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable excipients, wherein the drug is administered sublingually at a concentration of about 50-600 μg / αη. 2The diffusion flux delivers a dose of flumazenil over five minutes via a biological mucosa equivalent to the human oral mucosa. In some embodiments, the formulation delivers the target flux at a dose as low as approximately 2 mg / unit.

[0050] "Water-soluble polymer" can be a partially water-soluble polymer or a predominantly water-soluble polymer, a water-swellable polymer, or a combination of water-soluble and water-swellable polymers. The polymer can include cellulose or cellulose derivatives. Suitable examples of water-soluble polymers include, but are not limited to, polyethylene oxide, pachycarbamosan, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose, polyvinyl alcohol, water-swellable polysaccharides (such as starch), starch derivatives (such as polymers of dextrose, like maltodextrin), carrageenan, xanthan gum, locust bean gum, gum arabic, chitosan, alginate, hyaluronic acid, pectin, and combinations thereof. In some embodiments, the water-soluble polymer is a cellulose polymer, maltodextrin, polyethylene oxide, and combinations thereof. The cellulose polymer used in combination with polyethylene oxide and maltodextrin may be selected from the group consisting of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC). The combination of polyethylene oxide polymers with hydrophilic cellulose polymers and maltodextrin achieves a membrane with good adhesion, flexibility, and strength.

[0051] It may contain a "water-soluble polymer component" in an amount ranging from about 5% to 75% w / w, about 35% to 75% w / w, or about 40% to 70% w / w of the total weight of the formulation.

[0052] When present in a formulation, it may contain polyethylene oxide in an amount ranging from about 0% to 20% by weight of the water-soluble polymer component, about 1% to 15% by weight of the water-soluble polymer component, or about 10% to 15% by weight of the water-soluble polymer component.

[0053] Plasticizers can be incorporated to impart flexibility, enhance elasticity, and reduce brittleness. In some embodiments, plasticizers include triacetin, citrate derivatives (such as triethyl citrate, tributyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, trioctyl citrate, acetyl trioctyl citrate, trihexyl citrate, etc.), dibutyl sebacate, glycerol, polyethylene glycol, propylene glycol, or combinations thereof. Plasticizers can be contained in amounts ranging from about 0% to 20% w / w, about 2% to 15% w / w, or about 3% to 12% w / w of the formulation.

[0054] Mucosal adhesive polymers for adhesion to mucous membranes may be added, wherein the mucosal adhesive polymers are selected from the group consisting of: chitosan, hyaluronic acid salts, alginate, gelatin, collagen, poly(acrylic acid), poly(methacrylic acid), poly(L-lysine), poly(ethylene imine), poly(ethylene oxide), poly(2-hydroxyethyl methacrylate), and their salts or copolymers.

[0055] In some embodiments, the formulation comprises at least one flavoring agent selected from natural and synthetic flavoring liquids. Exemplary lists of such agents include volatile oils, synthetic flavoring oils, flavoring agents, oils, liquids, oleoresins, or extracts derived from plants, leaves, flowers, fruits, stems, and combinations thereof. A non-limiting representative list of examples includes peppermint oil, cocoa butter, and citrus oils (such as lemon, orange, grape, lime, and grapefruit), as well as fruit flavorings, including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, or other fruit flavoring agents.

[0056] In some embodiments, the formulation incorporates at least one sweetener selected from the following non-limiting list: glucose (corn syrup), dextrose, invert sugar, fructose, and combinations thereof; saccharin and its various salts, such as sodium salts; dipeptide sweeteners, such as aspartame; dihydrochalcone compounds, glycyrrhizin; stevia (stevioside); chlorinated derivatives of sucrose, such as sucralose; sugar alcohols, such as sorbitol, mannitol, xylitol, etc. Hydrogenated starch hydrolysates and synthetic sweeteners 3,6-dihydro-6-methyl-111,2,3-oxathiazin-4-one-2,2-dioxide, particularly its potassium salt (acetylsupan potassium) and its sodium and calcium salts, are also contemplated.

[0057] In some embodiments, the formulation incorporates at least one diluent selected from the group consisting of mannitol, microcrystalline cellulose (MCC), lactose, and combinations thereof. In some embodiments, the diluent is mannitol. In some embodiments, the formulation incorporates at least one surfactant / nonionic solubilizer selected from the group consisting of poloxamer, polyoxyethylene hydrogenated castor oil, glyceryl-based polyethylene glycol oxystearate, fatty acid glyceryl-based polyglycerol ester, polyglycerol ester, and combinations thereof. A colorant (e.g., dye) may be added. Dyes suitable for use in pharmaceutical compositions may include, for example, natural dyes such as annatto, anthocyanins, β-carotene, β-APO 8, carotene aldehyde, blackcurrant, caramel, canthaxanthin, caramel, pharmaceutical charcoal, carmine, carmine blue, carmine acid, carrot, chlorophyll, chlorophyll, cochineal extract, copper chlorophyll, copper chlorophyll, curcumin, curcumin / CU-chloro, elderberry, grape, hibiscus, lutein, mixed carotenoids, capsicum, riboflavin, titanium dioxide, turmeric, natural pigments, chokeberry / red berry, beet juice pigment, capsicum extract, capsicum oleoresin; or artificial dyes such as Allura Red, Brilliant Blue FCF, Amaranth, Azorubine, Fast Red E, Erythrosine, Green S, Patent Blue V, Ponceau 4R, Quinoline Yellow, Red 2G, Sunset Yellow, FD&C Yellow, and Tartrazine.

[0058] method

[0059] This document provides a method for reversing disability caused by intentional poisoning, comprising administering to a subject who has experienced a poisoning event one or more rapidly degradable unit formulations or nasal sprays, wherein the unit formulation and the nasal spray contain flumazenil. In some embodiments, the administration to the subject may be performed by the subject or a third party.

[0060] In some embodiments, the unit dosage form can be any formulation provided herein. In some embodiments, the unit dosage form contains an amount of flumazenil of about 0.18 mg to about 0.3 mg, and is administered as a total dose of 1 to 5 unit dosage forms within about 10 to about 40 minutes after the subject becomes aware that a poisoning event has occurred. In some embodiments, the unit dosage form also contains one or more pharmaceutically acceptable excipients. In some embodiments, the unit dosage form is selected from the group consisting of: tablets, lollipops, sublingual films, and lozenges.

[0061] In some embodiments, each unit dosage form contains approximately 0.8 mg to approximately 1.0 mg of flumazenil, and wherein the unit dosage form is a sublingual film that degrades in the mouth within 3-6 minutes. In some embodiments, the sublingual film has a concentration of approximately 75-110 μg / cm³. 2 A diffusion flux of approximately 30-65 μg / cm³. In some embodiments, the sublingual film formulation has a diffusion flux of approximately 30-65 μg / cm³. 2The diffusion flux is approximately 10-30 μg / cm³. In some embodiments, the sublingual film comprises about 0.9 mg of flumazenil and one or more pharmaceutically acceptable excipients, and wherein the sublingual film has a diffusion flux of approximately 10-30 μg / cm³. 2 diffusion flux per minute.

[0062] In some embodiments, the poisoning event involves administering a disabling drug to the subject. In some embodiments, 1 to 5 units are administered. In some embodiments, the disabling drug is a GABA agonist. In some embodiments, the GABA agonist is selected from the group consisting of: flunitrazepam, midazolam, triazolam, diazepam, γ-hydroxybutyric acid, zolpidem, zaleplon, and zopiclone.

[0063] List of implementation plans

[0064] The following non-limiting enumerations are merely exemplary embodiments of the invention provided herein and do not limit any aspect of this disclosure in any way.

[0065] Implementation scheme I-1: A method for reversing involuntary poisoning-induced disability, comprising administering a rapidly degradable formulation of flumazenil in unit form or as a nasal spray.

[0066] Implementation Scheme I-2: The method for reversing incapacitated by intentional poisoning as described in Implementation Scheme I-1, wherein each unit of the multi-unit flumazenil formulation contains an administered dose of flumazenil of 0.18 mg to approximately 0.3 mg, and the total dose ingested within a 10-40 minute opportunity window following awareness of the poisoning event is up to 5 unit doses.

[0067] Implementation Scheme I-3: A method for reversing incapacitated by intentional poisoning as described in Implementation Scheme I-1, wherein a potential victim is able to ingest up to 5 units of a dosage form within a maximum 40-minute window to reverse a large amount of date rape drugs ingested.

[0068] Implementation Scheme I-4: The method for reversing deliberate poisoning-induced disability as described in Implementation Scheme I-1, wherein the rapidly degrading agent is selected from the group consisting of: dissolving tablets, lollipop-like substances, sublingual tablets, and oral films that dissolve on the inside of the cheek.

[0069] Implementation Scheme I-5: The method for reversing deliberate poisoning-induced incapacity as described in Implementation Scheme I-1, wherein each unit dose of the flumazenil formulation is ingested once, and the formulation, which rapidly degrades in the mouth within 3-6 minutes, contains approximately 0.8 mg to approximately 1.0 mg of flumazenil.

[0070] Implementation Scheme I-6: The method for reversing intentional poisoning-induced disability as described in Implementation Scheme I-5, wherein the sublingual drug formulation of flumazenil contains 0.8 mg to 1.0 mg of flumazenil and pharmaceutically acceptable excipients, with a diffusion flux of approximately 75-110 μg / cm² / min.

[0071] Implementation Scheme I-7: A method for reversing involuntary poisoning-induced disability as described in Implementation Scheme I-6, wherein the sublingual drug formulation of flumazenil in unit dosage form comprises 0.8 mg to 1.0 mg of flumazenil and pharmaceutically acceptable excipients, with a diffusion flux of approximately 30-65 μg / cm² / min.

[0072] Implementation Scheme I-8: The method for reversing intentional poisoning-induced disability as described in Implementation Scheme I-5, wherein the sublingual drug formulation of flumazenil comprises 0.9 mg of flumazenil and a pharmaceutically acceptable excipient, with a diffusion flux of approximately 10-30 μg / cm² / min.

[0073] Implementation Scheme I-9: A treatment formulation for reversing intentional incapacitation in dating rape within a therapeutic window, comprising a multi-unit dosage form of a rapidly degradable formulation having 0.18 mg to 0.3 mg of flumazenil in a formulation that rapidly degrades in the mouth within 3-6 minutes.

[0074] Implementation Scheme I-10: A treatment formulation for reversing intentional incapacitation in dating rape within a therapeutic window, as described in Implementation Scheme I-9, wherein the sublingual film formulation of flumazenil comprises 0.18 mg to 0.3 mg of flumazenil and pharmaceutically acceptable excipients, with a diffusion flux of approximately 75-110 μg / cm³. 2 / min.

[0075] Implementation Scheme I-11: A treatment formulation for reversing intentional incapacitation in dating rape within a therapeutic window, as described in Implementation Scheme I-10, wherein the sublingual film formulation of said flumazenil in unit dosage form comprises 0.18-0.3 mg of flumazenil and pharmaceutically acceptable excipients, with a diffusion flux of approximately 30-65 μg / cm³. 2 / min.

[0076] Implementation Scheme I-12: A treatment formulation for reversing intentional incapacitation in dating rape within a therapeutic window, as described in Implementation Scheme I-9, wherein the sublingual film formulation of flumazenil comprises 0.2 mg of flumazenil and pharmaceutically acceptable excipients, with a diffusion flux of approximately 10-30 μg / cm³. 2 / min.

[0077] Implementation Scheme I-13: A treatment formulation for reversing intentional incapacitation in dating rape within a therapeutic window, comprising a multi-unit dosage form of a rapidly degradable formulation having about 0.8 mg to about 1.0 mg of flumazenil in a formulation that rapidly degrades in the mouth over 3-6 minutes.

[0078] Implementation Scheme I-14: A treatment formulation for reversing intentional incapacitation in dating rape within a therapeutic window, as described in Implementation Scheme I-13, wherein the sublingual film formulation of flumazenil comprises 0.8 mg to 1.0 mg of flumazenil and pharmaceutically acceptable excipients, with a diffusion flux of approximately 75-110 μg / cm³. 2 / min.

[0079] Implementation Scheme I-15: A treatment formulation for reversing intentional incapacitation in dating rape within a therapeutic window, as described in Implementation Scheme I-14, wherein the sublingual film formulation of said flumazenil in unit dosage form comprises 0.8 mg to 1.0 mg of flumazenil and pharmaceutically acceptable excipients, with a diffusion flux of approximately 30-65 μg / cm³. 2 / min.

[0080] Implementation Scheme I-16: A treatment formulation for reversing intentional incapacitation in dating rape within a therapeutic window, as described in Implementation Scheme I-13, wherein the sublingual film formulation of flumazenil comprises 0.9 mg of flumazenil and pharmaceutically acceptable excipients, with a diffusion flux of approximately 10-30 μg / cm³. 2 / min.

[0081] Implementation scheme II-1: A rapidly dissolving formulation containing about 0.2 mg to about 2 mg of flumazenil, wherein the formulation is a tablet, lollipop, sublingual film or lozenge, and wherein the formulation degrades in the mouth within about 3-6 minutes.

[0082] Implementation scheme II-2: The rapid dissolving formulation as described in implementation scheme II-1, further comprising one or more pharmaceutically acceptable excipients.

[0083] Implementation scheme II-3: A sublingual film containing about 0.2 mg to about 2 mg of flumazenil, wherein the sublingual film degrades in the mouth within about 3-6 minutes.

[0084] Implementation scheme II-4: The sublingual film as described in implementation scheme II-3 further comprises one or more pharmaceutically acceptable excipients.

[0085] Implementation scheme II-5: A sublingual film containing about 0.18 mg to about 0.3 mg of flumazenil, wherein the sublingual film degrades in the mouth within about 3-6 minutes.

[0086] Implementation scheme II-6: The sublingual film as described in implementation scheme II-5 further comprises one or more pharmaceutically acceptable excipients.

[0087] Implementation Scheme II-7: A sublingual film preparation as described in Implementation Scheme II-13 or 14, wherein the sublingual film preparation has a concentration of approximately 75-110 μg / cm³. 2 diffusion flux per minute.

[0088] Implementation Scheme II-8: A sublingual film preparation as described in Implementation Scheme II-13 or 14, wherein the sublingual film preparation has a concentration of approximately 30-65 μg / cm³. 2 diffusion flux per minute.

[0089] Implementation scheme II-9: A sublingual film as described in implementation scheme II-13 or 14, wherein the sublingual film contains 0.2 mg of flumazenil and has a diffusion flux of about 10-30 μg / cm2 / min.

[0090] Implementation scheme II-10: A sublingual film containing about 0.8 mg to about 1.0 mg of flumazenil, wherein the sublingual film degrades in the mouth within 3-6 minutes.

[0091] Implementation scheme II-11: The sublingual film as described in implementation scheme II-18 further comprises one or more pharmaceutically acceptable excipients.

[0092] Implementation Scheme II-12: A sublingual film preparation as described in Implementation Scheme II-18 or 19, wherein the sublingual film preparation has a concentration of approximately 75-110 μg / cm³. 2 diffusion flux per minute.

[0093] Implementation Scheme II-13: A sublingual film preparation as described in Implementation Scheme II-18 or 19, wherein the sublingual film preparation has a concentration of approximately 30-65 μg / cm³. 2 diffusion flux per minute.

[0094] Implementation Scheme II-14: A sublingual film preparation as described in Implementation Scheme II-18 or 19, wherein the sublingual film preparation contains 0.9 mg of flumazenil, and wherein the sublingual film preparation has a concentration of approximately 10-30 μg / cm³. 2 diffusion flux per minute.

[0095] Implementation Plan II-15: A method for reversing involuntary poisoning-induced disability, comprising administering one or more rapidly degradable unit formulations or nasal sprays to a subject who has experienced a poisoning event, wherein the unit formulation and the nasal spray contain flumazenil.

[0096] Implementation scheme II-16: The method as described in implementation scheme II-15, wherein each unit dosage form contains an amount of flumazenil of about 0.18 mg to about 0.3 mg, and wherein a total dose of 1 to 5 unit dosage forms is administered within about 10 to about 40 minutes after the subject becomes aware that the poisoning event has occurred.

[0097] Implementation scheme II-17: The method as described in implementation scheme II-16, wherein the poisoning event includes administering a disabling drug to the subject.

[0098] Implementation scheme II-18: The method of any one of implementation schemes II-15 to II-17, wherein 1 to 5 unit dosage forms are administered within approximately 40 minutes of the subject experiencing the poisoning event.

[0099] Implementation scheme II-19: The method as described in implementation scheme II-16 or 17, wherein the incapacitating drug comprises a GABA agonist.

[0100] Implementation scheme II-20: The method as described in implementation scheme II-19, wherein the GABA agonist is selected from the group consisting of: flunitrazepam, midazolam, triazolam, diazepam, γ-hydroxybutyric acid, zolpidem, zaleplon, and zopiclone.

[0101] Implementation scheme II-21: The method of any one of implementation schemes II-15 to II-20, wherein the unit dosage form further comprises one or more pharmaceutically acceptable excipients.

[0102] Implementation scheme II-22: The method of any one of implementation schemes II-15 to II-21, wherein the unit dosage form is selected from the group consisting of: tablets, lollipops, sublingual films and lozenges.

[0103] Implementation scheme II-23: The method as described in implementation scheme II-22, wherein each unit dosage form contains about 0.8 mg to about 1.0 mg of flumazenil, and wherein said unit dosage form is a sublingual film that degrades in the mouth within 3-6 minutes.

[0104] Implementation Scheme II-24: The method as described in Implementation Scheme II-23, wherein the sublingual film has a concentration of approximately 75-110 μg / cm³. 2 diffusion flux per minute.

[0105] Implementation Scheme II-25: The method as described in Implementation Scheme II-23, wherein the sublingual film has a concentration of approximately 30-65 μg / cm³. 2 diffusion flux per minute.

[0106] Implementation Scheme II-26: The method as described in Implementation Scheme II-22, wherein the sublingual film comprises about 0.9 mg of flumazenil and one or more pharmaceutically acceptable excipients, and wherein the sublingual film has a concentration of about 10-30 μg / cm³. 2 diffusion flux per minute.

[0107] Example

[0108] Example 1: Sublingual film containing 1 mg, 0.8 mg and 0.2 mg doses of flumazenil.

[0109] Table 1.1: Exemplary flumazenil formulations:

[0110] Element For the range of 1 mg flumazenil % For the range of 0.8 mg flumazenil % For the range of 0.2 mg flumazenil % Flumazenil 4.2% 3.8% 1% Maltodextrin 8%-10% 8%-10% 8%-10% Polyethylene oxide 5%-10% 5%-10% 5%-10% Sucralose 5%-10% 5%-10% 5%-10% Mannitol 4%-7% 4%-7% 4%-7% Hydroxypropyl methylcellulose 35%-50% 35%-50% 35%-50% polyethylene glycol 7%-15% 7%-15% glycerin 6%-13% Peppermint Supreme 1%-3% 1%-3% 0.8%-2.5% Purified water Appropriate amount Appropriate amount Appropriate amount

[0111] Preparation method:

[0112] 1. Disperse flumazenil in purified water and ethanol.

[0113] 2. Add the maltodextrin to step 1 and stir for 3-5 minutes.

[0114] 3. Add polyethylene oxide to step 2 and stir for 3-5 minutes.

[0115] 4. Add sucralose to step 3 and stir for 3-5 minutes.

[0116] 5. Add mannitol to step 4 and stir for 3-5 minutes.

[0117] 6. Add hydroxypropyl methylcellulose, polyethylene glycol / glycerin and strong peppermint to step 5 and stir for 5-10 minutes to form a slurry.

[0118] 7. Lay the slurry from step 6 onto the polyethylene sheet and

[0119] Dry at 90℃ for 10-20 minutes to obtain a sublingual film.

[0120] The following approximate drug throughput characteristics of the above formulation are expected:

[0121] Table 1.2:

[0122] Composition <![CDATA[Cumulative flux (mg / cm 2 ) during the 10-min diffusion period Flumazenil film 0.2 mg 2.6 Flumazenil film 0.8 mg 10 Flumazenil film 1 mg 100

[0123] Example 2: Additional sublingual film containing 1 mg, 0.8 mg and 0.2 mg doses of flumazenil.

[0124] Table 2.1: Exemplary Flumazenil Formulations

[0125] Element For the range of 1 mg flumazenil % For the range of 0.8 mg flumazenil % For the range of 0.2 mg flumazenil % Flumazenil 4.7% 3.76% 0.94% Maltodextrin 2%-8% 1%-7% 1%-6% Polyethylene oxide 5%-10% 4%-8% 4%-9% Sucralose 4%-10% 5%-9% 4%-8% Mannitol 2%-7% 3%-8% Polyhydroxylated castor oil 6%-12% 6%-13% Hydroxypropyl methylcellulose 30%-55% 38%-55% 45%-55% polyethylene glycol 7%-15% 7%-15% glycerin 10%-18% Strong Peppermint 1%-3% 1%-3% 0.8%-2.5% Vanilla flavoring 6%-13% Purified water Appropriate amount Appropriate amount Appropriate amount

[0126] Table 2.2. Other exemplary flumazenil formulations:

[0127] Element For the range of 1 mg flumazenil % For the range of 0.8 mg flumazenil % For the range of 0.2 mg flumazenil % Flumazenil 2% 1.6% 0.4% Maltodextrin 3% 3% 4% Polyethylene oxide 4% 3% 4% Sucralose 5% 3% 4% Polyhydroxylated castor oil 3% 5% 5% Hydroxypropyl methylcellulose 13.9% 18.9% 16.1% glycerin 3% 4% 4% Strong Peppermint 1% 1% 0.8% FD&C Yellow 0.1% 0.1% 0.1% Purified water Appropriate amount Appropriate amount Appropriate amount

[0128] Example 3: Tablets containing 1 mg, 0.8 mg and 0.2 mg doses of flumazenil.

[0129] Flumazenil tablets or lollipop-like forms can be based on powder compression or hard caramel. For compressed tablets, sugar substitutes, particularly isomaltose, sorbitol, or polydextrose, can be used. For hard sweet bases, fructose and / or glucose syrup can be used as sugar-free sugar substitutes, and sugar alcohols, such as maltitol or isomaltitol, can be used in particular. Different amounts of sweeteners (e.g., aspartame, acetylsupan, cyclamate, saccharin, or xylitol) can be added. Other excipients and active ingredients are incorporated into the matrix, and the tablets are produced using known manufacturing methods.

[0130] In the case of compressed powder mixtures, the excipients are weighed according to the formulation and mixed with the matrix. In the case of liquid excipients or active substances, these excipients may be added by means of a further granulation step. The powder or granules are then compressed to form tablets. The excipients or active substances may be compressed together or separately into one or more layers (1-layer, 2-layer, or 3-layer tablets), depending on the option.

[0131] In the case of hard caramel, the raw materials can be mixed according to the prescription and incorporated into a heated hard caramel base. In another step, shortly before final mixing and tablet formation, heat-sensitive excipients and / or active substances are added, particularly viscous agents (such as Icelandic moss), astringent active substances (such as alum), optional flavoring agents, optional coloring agents, and optional stabilizers, particularly tartaric acid or citric acid. Using these methods, sugar-free tablets containing varying amounts of astringents and viscous agents are produced, for example, as shown in the table below:

[0132] Table 3.1: Flumazenil Tablets A

[0133] raw material Dosage per tablet (mg) Flumazenil 1.0, 0.8, or 0.2 silicon dioxide 8 Lemon flavoring 30 Menthol 2 talc 50 Polyethylene glycol (macrogol) 25 alum 5 Icelandic moss extract 80 total 125

[0134] Single-layer ingots can be produced by powder pressing.

[0135] Table 3.2: Flumazenil tablets B based on hard caramel containing 5 mg alum and 80 mg Icelandic moss extract.

[0136] raw material Dosage per tablet (mg) Flumazenil drug extract 1.0, 0.8, or 0.2 Peach flavoring 15 Menthol 0.5 Citric acid 35 Sucralose 1.5 alum 5 Icelandic moss extract 80 total 142

[0137] Single-layer ingots can be produced by powder pressing.

Claims

1. A rapidly dissolving formulation comprising about 0.2 mg to about 2 mg of flumazenil, wherein the formulation is a tablet, lollipop, sublingual film, or lozenge, and wherein the formulation degrades in the mouth within about 3-6 minutes.

2. The rapidly dissolving formulation of claim 1, further comprising one or more pharmaceutically acceptable excipients.

3. A sublingual film containing about 0.2 mg to about 2 mg of flumazenil, wherein the sublingual film degrades in the mouth within about 3-6 minutes.

4. The sublingual film formulation of claim 2, further comprising one or more pharmaceutically acceptable excipients.

5. A sublingual film containing about 0.18 mg to about 0.3 mg of flumazenil, wherein the sublingual film degrades in the mouth within about 3-6 minutes.

6. The sublingual film formulation of claim 5, further comprising one or more pharmaceutically acceptable excipients.

7. The sublingual film as claimed in claim 5 or 6, wherein the sublingual film has a concentration of about 75-110 μg / cm³. 2 diffusion flux per minute.

8. The sublingual film as claimed in claim 5 or 6, wherein the sublingual film has a concentration of about 30-65 μg / cm³. 2 diffusion flux per minute.

9. The sublingual film of claim 5 or 6, wherein the sublingual film comprises 0.2 mg of flumazenil and has a concentration of approximately 10-30 μg / cm³. 2 diffusion flux per minute.

10. A sublingual film containing about 0.8 mg to about 1.0 mg of flumazenil, wherein the sublingual film degrades in the mouth within 3-6 minutes.

11. The sublingual film formulation of claim 10, further comprising one or more pharmaceutically acceptable excipients.

12. The sublingual film of claim 10 or 11, wherein the sublingual film has a concentration of about 75-110 μg / cm³. 2 diffusion flux per minute.

13. The sublingual film of claim 10 or 11, wherein the sublingual film has a concentration of about 30-65 μg / cm³. 2 diffusion flux per minute.

14. The sublingual film of claim 10 or 11, wherein the sublingual film comprises 0.9 mg of flumazenil, and wherein the sublingual film has a concentration of about 10-30 μg / cm³. 2 diffusion flux per minute.

15. A method for reversing involuntary poisoning-induced disability, comprising administering one or more rapidly degradable unit formulations or nasal sprays to a subject who has experienced a poisoning event, wherein the unit formulation and the nasal spray contain flumazenil.

16. The method of claim 15, wherein each unit dosage form comprises an amount of flumazenil of about 0.18 mg to about 0.3 mg, and wherein a total dose of 1 to 5 unit dosage forms is administered within about 10 to about 40 minutes after the subject becomes aware that the poisoning event has occurred.

17. The method of claim 16, wherein the poisoning event includes administering a debilitating drug to the subject.

18. The method of any one of claims 15 to 17, wherein 1 to 5 unit doses are administered within approximately 40 minutes of the subject experiencing the poisoning event.

19. The method of claim 17 or 18, wherein the incapacitating drug comprises a GABA agonist.

20. The method of claim 19, wherein the GABA agonist is selected from the group consisting of: flunitrazepam, midazolam, triazolam, diazepam, γ-hydroxybutyric acid, zolpidem, zaleplon, and zopiclone.

21. The method of any one of claims 15 to 20, wherein the unit dosage form further comprises one or more pharmaceutically acceptable excipients.

22. The method of any one of claims 15 to 21, wherein the unit dosage form is selected from the group consisting of: tablets, lollipops, sublingual films, and lozenges.

23. The method of claim 22, wherein each unit dosage form comprises about 0.8 mg to about 1.0 mg of flumazenil, and wherein the unit dosage form is a sublingual film that degrades in the mouth within 3-6 minutes.

24. The method of claim 23, wherein the sublingual film has a concentration of about 75-110 μg / cm³. 2 diffusion flux per minute.

25. The method of claim 23, wherein the sublingual film has a concentration of about 30-65 μg / cm³. 2 diffusion flux per minute.

26. The method of claim 22, wherein the sublingual film comprises about 0.9 mg of flumazenil and one or more pharmaceutically acceptable excipients, and wherein the sublingual film has a concentration of about 10-30 μg / cm³. 2 diffusion flux per minute.