Non-injectable formulations and method for delivery of some basic drugs

Abstract

Formulations comprising N-acetylcysteine, structural analogs, and / or derivatives thereof and basic drugs having a pKA of at or greater than 7.5 and molecular weight of around 650 or lower. Methods of delivering formulations comprising a combination of N-acetylcysteine, compounds of structural features similar to N-acetyl, and derivative, and / or combinations, thereof and basic drugs having a pKA of at or greater than 7.5, or at least 7.5, and a molecular weight of around 650 or lower either by buccal delivery or sublingual delivery are described. Provided is a buccal delivery platform.

Description

Non-injectable Formulations and Method for Delivery of Some Basic DrugsCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is an international patent application filed in accordance with the patent cooperation treaty. This application claims the priority benefit of U.S. Provisional Patent Application Nos. 63 / 566,380, filed 17 March 2024, and entitled “BUCCAL DELIVERY PLATFORM FOR BASIC DRUGS”, and 63 / 566,381, filed 17 March 2024, and entitled “Epinephrine Formulations and Methods of Treatment using Buccal Delivery”. The disclosure of U.S. Provisional Patent Application Nos. 63 / 566,380 and 63 / 566,381 are incorporated herein by reference in their entirety.FIELD OF THE INVENTION

[0002] The present invention relates to formulations comprising a combination of an acid with mucolytic properties, such as acetylcysteine, and a basic drug, such as epinephrine. Also described herein are methods of delivering the formulations to the oral cavity by buccal administration.BACKGROUND

[0003] While injecting a drug directly into the circulation can elicit rapid pharmacological effects and help bypass metabolism in the liver, the level of discomfort and risk of adverse effects are higher for an injection compared to most other routes of administration. In contrast, oral administration is generally much more comfortable for the patient, but results in much slower absorption and, often, loss of drug due to prolonged exposure to the highly acidic pH in the stomach, digestive enzymes during its passage through the gastrointestinal tract and, finally, metabolism in the liver, before the drug can reach systemic blood circulation.SUMMARY

[0004] Buccal delivery provides the ease of oral administration with the rapid effect of an injection. The inventors have recognized that acidic compounds with mucolytic properties and basic drugs can be prepared in formulations that can be delivered by buccal administration.

[0005] The oral cavity is supplied by a dense network of blood vessels. The wet soft tissue membrane that lines the entire oral cavity comprises the oral mucosa, and within the oral cavity, the region comprising the inner lining of the cheeks near the floor of the mouth is called the buccal mucosa. The outermost layer of cells closest to the surface is called the oral epithelium, whose thickness varies by location. The blood vessels in the space between the cheeks and gum, as well as the oral floor, are oriented parallel and make maximum contact with the epithelium, making these regions suitable for the rapid permeation of some small molecule drugs. See, forexample, Naumova EA, Dierkes T, Sprang J, Arnold WH. The oral mucosal surface and blood vessels. Head Face Med. 2013 Mar 12; 9:8. Absorption through buccal epithelium spares the drug from liver metabolism, as well. A thin biofilm or mucus layer covers the oral mucosa, protecting the underlying tissue. This mucus layer is composed of saliva, mucin, various proteins, digesting enzymes, as well as bacteria. Although relatively thinner than in the gastrointestinal regions, the mucus layer of the buccal and sublingual regions also need to be penetrated by the drugs for adequate buccal absorption.

[0006] Drug molecules intended to treat a disease inside our body almost always need access to the internal organs or the diseased tissue ‘compartment(s)’ to elicit their effect. For most treatments, the drugs reach these target compartments through the circulating blood and extracellular fluids following absorption from the gastrointestinal tract - as in the case of orally administered drugs, or are directly ‘pushed’ into circulation, by injection. Where rapid action against the disease is needed, as in the case of acute health emergencies, the drugs are often injected directly into the circulation to reduce the time taken by the drug to traverse various absorption barriers before reaching the circulation. Albeit rare, the speed and efficiency of injection can sometimes be approached by buccal and intranasal routes of administration, as well. In contrast to injections, these routes offer significant advantages in patient comfort and ease of administration. These regions are heavily vascularized, have thinner barrier membranes and the drugs entering the circulatory routes accessible from these regions do not first traverse the liver, where they could otherwise be metabolized and rendered inactive. Yet, success in the delivery of drugs through the buccal mucosa or by the intranasal route of administration has been rare due to the substantial technical barriers that need to be overcome.

[0007] Examples of drugs that require rapid absorption are, for example, adrenergic stimulant drugs such as epinephrine. Epinephrine (also known as adrenaline) is an endogenous catecholamine with potent a- and P-adrenergic stimulating properties. The P-adrenergic property increases systemic (both systolic and diastolic blood pressures) and pulmonary vascular resistance, while the p-adrenergic effect increases myocardial contractility, heart rate, relaxes smooth muscle in the skeletal muscle vascular bed and in the bronchi. Secreted by the adrenal glands in response to stress, epinephrine or adrenaline plays a vital role in acute stress response by stimulating the sympathetic nervous system.

[0008] Epinephrine is currently approved for the emergency treatment of type 1 hypersensitivity reactions, including anaphylaxis, induction, and maintenance of mydriasis during intraocular surgeries and hypotension due to septic shock. It is also used to treat ventricular fibrillation, pulseless ventricular tachycardia, asystole, pulseless electrical activity (PEA), croup, and severeasthma exacerbations unresponsive to standard treatment. Sometimes, the vasoconstriction effect on capillaries is used to extend local anesthetic effect or to arrest bleeding.

[0009] Despite the advantages it offers, only a handful of drugs are currently delivered by the buccal and sublingual routes of administration. Smaller surface area and the continuous secretion of saliva are some of the challenges encountered in buccal drug delivery. Compared to the gastrointestinal tract which has an effective surface area of ca. 250m2for the absorption of a drug, the surface area of the oral mucosa is only around 170cm2, more than 3 order of magnitude smaller. The buccal and sublingual regions are even smaller, comprising only a third of the total surface area of the oral cavity. See Chinna Reddy P, Chaitanya KS, Madhusudan Rao Y. A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods. Daru. 2011 ; 19(6) :385-403. Continuous secretion of up to 2L of saliva per day in the oral cavity that is accentuated in the presence of food or drug dosage forms is yet another challenge for buccal drug delivery. The saliva of the mouth not only dilutes the dissolving drug, thus negatively impacting passive diffusion through the oral epithelium, but also washes the contents of the mouth down the gastrointestinal tract facilitated by the involuntary act of swallowing. The swallowed drug follows the same fate of slow and poor absorption, as other orally administered products.

[0010] Conventional methods of buccal drug delivery have relied on fast dissolving oral tablets and thin films, often with an added mucoadhesive component, to prolong the retention of the dosage form in the oral cavity while the dissolution and absorption of the drug takes place. Many mucoadhesive polymers have been considered for buccal delivery, including various polyacrylic acid-based polymers, modified starches, dextran and its derivatives, chitosan and its derivatives, various natural gums like xanthan and alginates. More recently, proteins like lectins that are extensively involved in biological processes involving intercellular recognition and binding have also been shown to promote mucoadhesion conducive to buccal delivery. Yet, despite the longer retention of the dosage form due to its adhesion to the buccal mucosal epithelium, the propensity for the dissolved drug to be washed into the gastrointestinal tract or be swallowed is not lessened.

[0011] Epinephrine has very low oral bioavailability and is mostly administered by injection. However, the free base form of epinephrine is only sparingly soluble in aqueous media at or near neutral pH and requires acid solutions and a low pH to dissolve. As a result, epinephrine formulations that are adjusted to lower pH can cause pain and discomfort at the site of injection. If the solubility is not sufficiently high, the dose volume of the injected liquid could be relatively high and require relatively longer time (several seconds) to inject completely from autoinjectiondevices, such as EPIPEN. Hence, administration of epinephrine by injection in emergencies, even with autoinjectors, can be an uncomfortable exercise for both the patient and the person administrating the dose, if different, and can sometimes result in underdosing.

[0012] Among small molecule therapeutics, most drugs have one or more ionizable functional groups and tend to carry a charge at pH values encountered in various cellular and extracellular media. Due to the lipophilic nature of cellular membranes, such as the outer epithelial membranes, the passive diffusion and absorption of these small molecule drugs even through relatively thin epithelial membranes can be negatively impacted by ionization. For absorption through lipid membranes by passive diffusion, drugs that are nonionized and more lipophilic are considered to offer an advantage. In addition to the lipoid nature of the membrane, the intranasal and the oral epithelial membranes are bathed in a viscous gel-like glycoprotein secretion called mucus. This mucus layer presents an additional barrier to diffusion, and for the access to the epithelium for most foreign bodies, microbes, as well as drugs. Since the mucus secretion carries a net negative charge, basic drugs that also carry a net negative charge are especially disadvantaged.

[0013] Certain inactive ingredients that promote drug permeability and commonly known as ‘penetration enhancers’ have also been explored in augmenting buccal drug delivery. Such penetration enhancers can be surface active agents, such as anionic molecules like sodium lauryl sulfate, or cationic surfactants like cetylpyridinium chloride, or nonionic surfactants like poloxamer, Brij, Span, Myij, or Tween. They can be fatty acids, like oleic acid, caprylic acid, lauric acid, lysophosphatidyl choline, or phosphatidyl choline. They can also be bile salts like sodium glycocholate, sodium taurodeoxycholate, sodium taurocholate, etc. Various cyclodextrins and chelators, like edetic acid salts, citric acid, sodium salicylate, methoxysalicylates have also been used as penetration enhancers. In their review of buccal delivery, P Chinna Reddy et al. (see Chinna Reddy P, Chaitanya KS, Madhusudan Rao Y. A review on bioadhesive buccal drug delivery systems: current status of formulation and evaluation methods. Daru. 2011 ;19(6):385-403. (2011) ) have also included various positively charged compounds like poly-L-arginine, L-lysine or cationic polymers like chitosan and trimethylchitosan as penetration enhancers for buccal drug delivery, due to their ability to interact with negatively charged mucin. In some cases, addition of enzyme inhibitors have been considered for the inhibition of digestive enzymes as a method to protect the drug from being metabolized before permeating through the buccal mucosa. See Alur HH. Peptides and proteins: buccal absorption. In: Swarbrick J, Boylan JC, editors. Encyclopedia of Pharmaceutical Technology. 3. Vol. 20. Marcel Dekker Inc; 2001. pp. 193-218.

[0014] Drug delivery strategies targeting the oral mucosa and intended for rapid absorption, often comprise fast dissolving oral tablets or films that would need to be retained in the mouth cavity for a few to several minutes for the tablet or film to disintegrate, dissolve, and for the drug to penetrate the mucosal barrier and then the epithelium. Sometimes, mucoadhesive components are added to promote adhesion to the mucus layer and to ensure that dosage form stays in the oral cavity and is not swallowed; the latter to prevent absorption through the GI tract, instead. Typically, drug molecules that can be rapidly delivered by the buccal and the intranasal routes are limited to those that require very low doses, are low molecular weight, and are non-ionized or relatively non-polar at neutral pH and have sufficient solubility to dissolve the dose, for rapid diffusion and passive absorption. For example, sublingually administered tablets of the vasodilator, nitroglycerin, used for the treatment of acute attacks of angina pectoris associated with coronary artery disease can deliver the drug rapidly into systemic circulation reaching peak plasma levels within 6 to 7 minutes. The log (base 10) octanol- water partition coefficient or LogP of nitroglycerin is around 1.6 indicating a fairly lipophilic molecule that has no ionizable groups. It has a molecular weight of 227 and, despite its low water solubility (ca. 1.25mg / mL), the doses in the range of only 0.3 to 0.6mg are sufficiently low to be dissolved in less than 0.5mL of water. In other cases, although hydrochloride salt forms for certain basic drugs, such as buprenorphine and naloxone are utilized to improve solubility and permeability for buccal absorption, these dosage forms suffer from poor bioavailability (ca. 30% for buprenorphine sublingual tablet and less than 10% for naloxone) and wide inter-patient variability.

[0015] Epinephrine is also prone to degradation over time, particularly at higher temperatures. Current marketed formulations of epinephrine (e.g., EPIPEN®) therefore have limited shelf-life, and cannot be stored without refrigeration in warmer climates. Degradation of the active compound is a significant problem because it also leads to underdosing, which could be lifethreatening. Many currently marketed formulations also contain sodium metabisulfite as an antioxidant, and / or chelants / chelators. Epinephrine’s poor solubility in water means that it is often formulated as the hydrochloric acid or tartaric acid salt at an acidic pH (typically with a pH <5, or less than 4.5). This limits how epinephrine can be administered.

[0016] It is therefore desirable to provide an alternative or improved epinephrine formulation. In particular, it is desirable to provide an epinephrine formulation for rapid delivery, including without the need for injecting the drug, such as by an intranasal route or by oral mucosal absorption.

[0017] The inventors have discovered, as described herein in various embodiments, a buccal delivery formulation comprising a basic drug and an acidic compound with mucolytic properties.The buccal delivery formulations, in various embodiments, are useful in treating hypersensitivity reactions. In various embodiments diseases such as cardiac arrest, anaphylaxis, bronchiolitis, asthma and croup can be treated with formulations described herein in various embodiments.

[0018] In some embodiments, of the buccal delivery formulation described herein, the acidic compound with mucolytic properties is an acetylcysteine. In various embodiments, the acetylcysteine is selected from the group consisting of N-acetyl-L-cysteine, a structural analog thereof, or a derivative thereof. In various embodiments, the acetylcysteine is N-acetyl-L-cysteine. In various embodiments, the basic drug has a pKa of 7.5 or higher. In various embodiments, the basic drug has a conjugate acid of having a pKa of 8 or higher. In some embodiments, the basic drug has a pKa of 7.5 or higher and a molecular weight of about 650 or less. In various embodiments, the basic drug is selected from epinephrine, norepinephrine, dopamine, phenylephrine, a local anesthetic, lidocaine, bupivacaine, sildenafil, albuterol, amiodarone, amitriptyline, orphenadrine, fentanyl, ixazomib, sildenafil, sufentanil, tamoxifen, tofacitinib, toremifene, albuterol, abacavir, amphetamines, atropine, clopidogrel, ephedrine, Larotrectinib, morphine, neostigmine, phenelzine, rimegepant selumetinib, terbutaline, and tranylcypromine, and combinations thereof. In some embodiments, the buccal delivery formulation comprises between about 0.01 wt.% and about 50 wt.% of the basic drug based on the total weight of the formulation. In some embodiments, the basic drug is epinephrine.

[0019] In some embodiments, the buccal delivery formulation is a liquid formulation. In some embodiments, the liquid formulation is a solution.

[0020] In some embodiments, the buccal delivery formulation comprises between about 0.001 wt.% to about 50 wt.% acetylcysteine, based on the total weight of the formulation.

[0021] In some embodiments of the buccal delivery formulation acetylcysteine and the basic drug are present as salts. In some embodiments of the buccal delivery formulation the amount of acetylcysteine is in molar excess of the basic drug. In some embodiments of the buccal delivery formulation, the pH of the formulation is between 3 and 8.

[0022] In some embodiments, the buccal delivery formulation comprises arginine in an amount of up to 1.5 wt.%, based on the total weight of the formulation. In some embodiments, the buccal delivery formulation comprises sodium bicarbonate in an amount of up to 2 wt.%, based on the total weight of the formulation.

[0023] In some embodiments, the buccal delivery formulation comprises a sweetener in an amount up to 2 wt.%, based on the total weight of the formulation. In some embodiments the sweetener is selected from the group consisting of saccharin, a saccharin salt, a sugar alcohol, a monosaccharide sugar, a disaccharide sugar, and combinations thereof. In some embodiments, the sweetener isselected from sucralose, xylitol, sucrose, mannitol, fructose, sodium saccharin, or combinations thereof.

[0024] In some embodiments, the buccal delivery formulation comprises cysteine or a cysteine salt in an amount of up to 1 wt.% based of the total weight of the formulation.

[0025] In some embodiments, the buccal delivery formulation is free of cysteine or cysteine salts. In some embodiments, The buccal delivery formulation is free of chelants or chelators. In some embodiments, the buccal delivery formulation is free of sulfates or sulfites. In some embodiments, the buccal delivery formulation is free of ascorbic acid, vitamin A, vitamin E, propylgallate, ascorbyl palmitate, butylated hydroxytoluene (BHT), citric acid, alkyl gallates, and gallic acid.

[0026] In some embodiments, the buccal delivery formulation comprises from about 1.25 wt.% to about 2 wt.% acetylcysteine, from about 0.25 to about 0.75 wt.% of the basic drug, up to about 1.5 wt.% arginine, up to about 2 wt.% sodium bicarbonate, and optionally up to about 2 wt.% sweetener, wherein all wt.% are based on the total weight of the formulation. In some embodiments, the buccal delivery formulation comprises from about 1.5 wt.% to about 1.8 wt.% acetylcysteine, from about 0.25 to about 0.75 wt.% of the basic drug, from about 0.1 wt.% to about 0.4 wt.% arginine, from about 0.25 wt.% to about 0.75 wt.% sodium bicarbonate, and optionally up to about 2 wt.% sweetener, wherein all wt.% are based on the total weight of the formulation.

[0027] In some embodiments, the buccal delivery formulation comprises from 1.25 wt.% to 2 wt.% acetylcysteine, from 0.25 to 0.75 wt.% of the basic drug, and up to 1.5 wt.% arginine, up to 2 wt.% sodium bicarbonate, and optionally up to 2 wt.% sweetener, wherein all wt.% are based on the total weight of the formulation. In some embodiments, the buccal delivery formulation comprises from 1.5 wt.% to 1.8 wt.% acetylcysteine, from 0.25 to 0.75 wt.% of the basic drug, from 0.1 wt.% to 0.4 wt.% arginine, from 0.25 wt.% to 0.75 wt.% sodium bicarbonate, and optionally up to 2 wt.% sweetener, wherein all wt.% are based on the total weight of the formulation.

[0028] In some embodiments, the buccal delivery formulation is a liquid solution suitable for injection, nasal, oral, ophthalmic, or buccal delivery. In some embodiments, the tonicity of the formulation is from about 100 mOsm / kg to 450 mOsm / kg. In some embodiments, the buccal delivery formulation comprises a tonicity adjuster, and wherein the tonicity of the formulation to 270 mOsm / kg to 320mOsm / kg, and optionally wherein the tonicity adjuster is selected from sodium chloride, potassium chloride, mannitol, glycerin, glucose or dextrose, optionally wherein the tonicity adjuster is sodium chloride.

[0029] In some embodiments, provided herein is a method of treating a disease associated with hypersensitivity reactions comprising administering to a subject in need thereof a therapeutically effective amount of the buccal delivery formulation described herein in various embodiments. Insome embodiments, provided herein is a method of treating cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup, comprising administering to a subject in need thereof a therapeutically effective amount of the buccal delivery formulation described herein in various embodiments. In some embodiments, the method of treating a disease associated with hypersensitivity reactions and / or selected from cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup comprising providing a dosage volume of the formulation in liquid form of less than 0.5 mL. In some embodiments, the amount of basic drug in solution is greater than 2.5 mg / mL.

[0030] In some embodiments, the method comprises delivering the formulation to the sublingual and / or oral vestibular space.

[0031] In some embodiments, the method of treating a disease associated with hypersensitivity reactions comprising administering to a subject in need thereof a therapeutically effective amount of a buccal delivery formulation described herein comprising acetylcysteine and a therapeutically effective amount of a basic drug.

[0032] In some embodiments, provided is a method of treating a disease selected from cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup comprising administering to a subject in need thereof a therapeutically effective amount of a buccal delivery formulation comprising acetylcysteine and a therapeutically effective amount of a basic drug. In some embodiments, acetylcysteine is N-acetyl-L-cysteine and the basic drug is epinephrine. In some embodiments, the basic drug has a pKa of 7.5 or higher. In some embodiments, the buccal delivery formulation comprises N-acetyl-L-cysteine (NAC), a structural analog of N-acetyl-L-cysteine, or derivatives thereof, and a basic drug having a pKa of 7.5 or higher and a molecular weight of about 650 or less. In some embodiments, the basic drug is selected from from epinephrine, norepinephrine, dopamine, phenylephrine, a local anesthetic, lidocaine, bupivacaine, sildenafil, albuterol, amiodarone, amitriptyline, orphenadrine, fentanyl, ixazomib, sildenafil, sufentanil, tamoxifen, tofacitinib, toremifene, albuterol, abacavir, amphetamines, atropine, clopidogrel, ephedrine, Larotrectinib, morphine, neostigmine, phenelzine, rimegepant selumetinib, terbutaline, and tranylcypromine, and combinations thereof.

[0033] In some embodiments, the buccal delivery formulation comprises a liquid buccal formulation. In some embodiments, the liquid buccal formulation is hypotonic. In some embodiments, about 120 and about 250 mOsm / kg. In some embodiments, the liquid buccal formulation comprises a sweetener in an amount from 0.02 wt.% to 0.06 wt.%. In some embodiments, the buccal delivery formulation is prepared using 0.01 wt.% to 2 wt.% acetylcysteine. In some embodiments, buccal delivery formulation is prepared using 0.25 to 0.75 wt.% of the basic drug. In some embodiments, buccal delivery formulation is formulated with adosage volume of less than 0.5 mL.

[0034] In some embodiments, provided herein is a method of delivering a liquid formulation to the buccal cells of a subject, wherein the method comprises administering to the oral cavity the buccal delivery formulation described herein in various embodiments. In some embodiments, provided herein is a method of delivering a liquid formulation to the buccal cells of a subject wherein the method comprises administering to the to the sublingual and / or oral vestibular space the buccal delivery formulation described herein in various embodiments.

[0035] In some embodiments, provided herein is a method of delivering a liquid formulation to the buccal cells of a subject, comprising administering to the oral cavity the buccal delivery formulation described herein in various embodiments.

[0036] In some embodiments, provided herein is a buccal delivery formulation for a basic drug comprising acetylcysteine. In some embodiments, the acetylcysteine is N-acetyl-L-cysteine, structural analogs, or derivatives thereof. In some embodiments, the acetylcysteine is N-acetyl-L- cysteine, structural analogs, derivatives thereof, or combinations thereof. In some embodiments, the buccal delivery formulation further comprises a basic drug. In some embodiments, the basic drug has a pKa of 7.5 or higher. In some embodiments, the basic drug has a molecular weight of about 650 or less. In some embodiments, the acetylcysteine is N-acetyl-L-cysteine (NAC).

[0037] Described herein, in various embodiments, is a method of buccal or sublingual delivery for small molecule basic drugs with at least one ionizing functional group with a pKa of around 7.9 and higher for the conjugate acid, such that the drug carries a net positive charge at neutral pH. These drugs in various embodiments are small molecules of molecular weight around 650 or lower that are also be capable of forming ion-pairs, i.e. salts with stronger acids with a pKa of 5.0 or lower.

[0038] In some embodiments, provided herein are combinations of basic drugs as described above with acetylcysteine. In various embodiments such a basic drug, as described in various embodiments, is combined with drug with acetylcysteine. In a particular embodiment acetylcysteine is N-acetyl-L-cysteine (NAC) (Figure below).

[0039] Structure of N-acetyl-L-cysteine (NAC).

[0040] N-acetyl-L-cysteine (IUPAC name: (2R)-2-acetamido-3-sulfanylpropanoic acid; Molecular Formula C5H9NO3S ; Molecular Weight 163.20 g / mol, CAS Number: 616-91-1), also known as acetylcysteine or mercaptopuric acid is the N-acetylated derivative of the natural amino acid L-cysteine. Pubchem lists NAC as an antiinfective agent, an antioxidant, an antiviral drug, an antidote to paracetamol poisoning, , a mucolytic agent, a human metabolite, a radical scavenger, a ferroptosis inhibitor and useful in the healing of wounds or against aging. It is an N- acetyl-L- amino acid and its conjugate acid is N-acetyl-L-cysteinate.

[0041] Molecules that resemble the structural features of NAC could also be used in the delivery method, and formulations, described herein. Such examples include N-acetyl derivatives of other L- or D- isomers of natural and synthetic amino acids with a thiol group. In other embodiments, the two-carbon acetyl group [ H3C-C=O-] linked to the nitrogen atom may be replaced by longer chain derivatives [R-C=O-], where R is an alkyl, or substituted alkyl chain, other unsaturated derivatives or may contain aromatic groups connected either directly or indirectly to the carbon of the carbonyl group linked to the nitrogen atom of the amino acid.

[0042] The carboxylic group in NAC has an estimated pKa of 3.24 and renders a solution of the molecule quite acidic (pH at 3 or lower). The thiol group has an estimated pKa of 9.52. The carboxylic functional group of NAC is capable of forming salts with certain basic small molecule drugs, such that the solubility of the salt form is higher than either NAC or the drug. In addition to the improved solubility, such salt forms of the basic drug with NAC is found to have superior buccal absorption properties, such that the entire dose of the drug can be administered as a liquid solution into the buccal or sublingual regions of the mouth for rapid absorption. Despite being a liquid, the delivered dose is absorbed and not washed away by the secretion of the saliva. Without wishing to be bound by theory, it is possible that the presence of the thiol functional group in NAC promotes interaction with the mucus layer and facilitates presentation of the penetrating drug to the close proximity of the underlying cellular epithelium in a high enough concentration for rapid absorption. Although polymers such as poly acrylates, chitosan or deacetylated gellan gum and their corresponding thiomers with added thiol functional groups have recently been investigated for buccal mucoadhesion and drug delivery, N-acetyl-L-cysteine (NAC) has never been considered to be a mucoadhesive molecule.

[0043] In various embodiments, the inventors recognize that drugs having a basic pKa (7.5 or higher) and a MW ca. 650 and lower, can be used in combination with N-acetyl-L-cysteine (NAC), molecules that resemble the structural features of NAC, and derivatives thereof. Combinations of drugs having a basic pKa (7.5 or higher) and a MW ca. 650 and lower with N- acetyl-L-cysteine (NAC), molecules that resemble the structural features of NAC, andderivatives thereof, can be used to prepare formulations for buccal delivery.

[0044] Examples of basic drugs that are particularly suitable for the delivery methods and formulations described herein in various embodiments, are those that treat acute conditions, have poor solubility in water as a free base, and would benefit from rapid absorption by a non- parenteral route. Drugs that can be used in various embodiments described herein, include, for example, morphine (pKa 8.21) and its derivatives, various opioids and opioid rescue agents, fentanyl (pKa 8.44), naloxone (pKa 7.94), naltrexone (pKa 10.2), various catecholamines, such as, epinephrine (pKa 8.6), norepinephrine (pKa 8.6) dopamine (pKa 8.93), phenylephrine (pKa 8.97) etc., local anesthetic drugs, such as, lidocaine (pKa 7.95), bupivacaine (pKa 8.1), and many diverse therapeutic classes of basic drugs, exemplified by at least one drug from each of these therapeutic classes, viz. sildenafil (pKa 8.7), albuterol (pKa 9.2), amiodarone (pKa 9.06), amitriptyline (pka 9.4). In various embodiments, any of these drugs, either alone, or in combination, can be combined with acetylcysteine, molecules that resemble the structural features of NAC as described herein, or, in some embodiments, derivatives of acetylcysteine, in formulations useful for buccal delivery, methods of buccal delivery, and / or methods of sublingual delivery.

[0045] The inventors recognize that other drugs would be suitable for the methods and formulations described herein. For example, orphenadrine (analgesic), fentanyl, ixazomib (proteosome inhibitor - multiple myeloma), sildenafil, sufentanil, tamoxifen (antiestrogenic, pKa 8.85), tofacitinib (Janus kinase or JAK inhibitor), toremifene (estrogen receptor modulator, pKa 7.76), albuterol, abacavir, amphetamines, atropine, clopidogrel (platelet receptor inhibitor), ephedrine, larotrectinib (kinase inhibitor), morphine, neostigmine (cholinesterase inhibitor), phenelzine (MAO inhibitor), rimegepant (peptide receptor antagonist for migraine), selumetinib, terbutaline, and tranylcypromine can be used in various formulations and methods described herein.

[0046] In some embodiments, provided herein is a buccal delivery formulationcomprising a basic drug and alsoacetylcysteine. In some embodiments, acetylcysteine is N-acetyl-L-cysteine. In some embodiments, the buccal delivery formulationfurther comprising a basic drug. In some embodiments, the basic drug has a pKa of 7.5 or higher. In some embodiments, the basic drug has a pKa of 7.9 or higher. In some embodiments, the basic drug has a pKa of at least 7.5. In some embodiments, the basic drug has a pKa of at least about 7.5. In some embodiments, the basic drug has a molecular weight of about 650 or less. In some embodiments, the buccal delivery formulationcomprises N-acetyl-L-cysteine (NAC), a compound of structural features similar to N-acetyl-L-cysteine, or derivatives thereof.

[0047] In some embodiments, provided herein is a buccal delivery formulationcomprising a basic drug and acetylcysteine. In some embodiments, the acetylcysteine is N-acetyl-L-cysteine. In some embodiments, the basic drug has a pKa of 7.5 or higher and a molecular weigh of 650 or less. In some embodiments of the buccal delivery formulationacetylcysteine is N-acetyl-L- cysteine (NAC), a compound of structural features similar to N-acetyl-L-cysteine, or derivatives thereof. In some embodiments, the basic drug is selected from from epinephrine, norepinephrine, dopamine, phenylephrine, a local anesthetic, lidocaine, bupivacaine, sildenafil, albuterol, amiodarone, amitriptyline, orphenadrine, fentanyl, ixazomib, sildenafil, sufentanil, tamoxifen, tofacitinib, toremifene, albuterol, abacavir, amphetamines, atropine, clopidogrel, ephedrine, Larotrectinib, morphine, neostigmine, phenelzine, rimegepant selumetinib, terbutaline, and tranylcypromine, and combinations thereof.

[0048] In some embodiments, the buccal delivery formulation is a liquid formulation.

[0049] In some embodiments, the liquid formulation is a solution. In some embodiments acetylcysteine is between about 0.001 wt.% to about 50 wt.% acetyl cysteine, based on the total weight of the formulation. In some embodiments, acetyl cysteine is an N-acetyl-L-cysteine or a derivative. In some embodiments, the buccal delivery formulationcomprises between about 0.01 wt.% and about 50 wt.% of the basic drug based on the total weight of the formulation.

[0050] In some embodiments, provided is a method of treating a disease, wherein the disease is associated with hypersensitivity reactions, and / or wherein the disease is selected from cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup, comprising administering to a subject in need thereof a therapeutically effective amount of a buccal delivery formulationcomprising acetyl cysteine and a therapeutically effective amount of a basic drug. In some embodiments, acetylcysteine is N-acetyl-L-cysteine. In some the basic drug has a pKa of 7.5 or higher. In some embodiments, acetylcysteine is N-acetyl-L-cysteine (NAC), a compound of structural features similar to N-acetyl-L-cysteine, or derivatives thereof.

[0051] In some embodiments, provided is a method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a buccal delivery formulationcomprising acetyl cysteine and a therapeutically effective amount of a basic drug selected from from epinephrine, norepinephrine, dopamine, phenylephrine, a local anesthetic, lidocaine, bupivacaine, sildenafil, albuterol, amiodarone, amitriptyline, orphenadrine, fentanyl, ixazomib, sildenafil, sufentanil, tamoxifen, tofacitinib, toremifene, albuterol, abacavir, amphetamines, atropine, clopidogrel, ephedrine, Larotrectinib, morphine, neostigmine, phenelzine, rimegepant selumetinib, terbutaline, and tranylcypromine, and combinations thereof.

[0052] Drugs that require rapid absorption are, for example, adrenergic stimulant drugs such asepinephrine, also could be used with the methods and formulations described herein.Epinephrine (also known as adrenaline) is an endogenous catecholamine with potent a- and P- adrenergic stimulating properties. The P-adrenergic property increases systemic (both systolic and diastolic blood pressures) and pulmonary vascular resistance, while the p-adrenergic effect increases myocardial contractility, heart rate, relaxes smooth muscle in the skeletal muscle vascular bed and in the bronchi. Secreted by the adrenal glands in response to stress, epinephrine or adrenaline plays a vital role in acute stress response by stimulating the sympathetic nervous system.

[0053] Epinephrine is currently approved for the emergency treatment of type 1 hypersensitivity reactions, including anaphylaxis, induction, and maintenance of mydriasis during intraocular surgeries and hypotension due to septic shock. It is also used to treat ventricular fibrillation, pulseless ventricular tachycardia, asystole, pulseless electrical activity (PEA), croup, and severe asthma exacerbations unresponsive to standard treatment. Sometimes, the vasoconstriction effect on capillaries is used to extend local anesthetic effect or to arrest bleeding.

[0054] Epinephrine has very low oral bioavailability and is mostly administered by injection. However, the free base form of epinephrine is only sparingly soluble in aqueous media at or near neutral pH and requires acid solutions and a low pH to dissolve. As a result, epinephrine formulations that are adjusted to lower pH can cause pain and discomfort at the site of injection. If the solubility is not sufficiently high, the dose volume of the injected liquid could be relatively high and require relatively longer time (several seconds) to inject completely from autoinjection devices, such as EPIPEN., Hence, administration of epinephrine by injection in emergencies, even with autoinjectors, can be an uncomfortable exercise for both the patient and the person administrating the dose, if different, and can sometimes result in underdosing.

[0055] Epinephrine is also prone to degradation over time, particularly at higher temperatures. Current marketed formulations of epinephrine (e.g., EPIPEN®) therefore have limited shelf-life, and cannot be stored without refrigeration in warmer climates. Degradation of the active compound is a significant problem because it also leads to underdosing, which could be lifethreatening. Many currently marketed formulations also contain sodium metabisulfite as an antioxidant, and / or chelants / chelators. Epinephrine’s poor solubility in water means that it is often formulated as the hydrochloric acid or tartaric acid salt at an acidic pH (typically with a pH <5, or less than 4.5). This limits how epinephrine can be administered.

[0056] Hence, it is desirable to provide an alternative or improved epinephrine formulation. In particular, it is desirable to provide an epinephrine formulation for rapid delivery, including without the need for injecting the drug, such as by an intranasal route or by oral mucosalabsorption.

[0057] In some embodiments, epinephrine formulations are provided herein in accordance with various embodiments, and such formulations can be delivered by the delivery methods provided herein. As with other drugs described herein, it is desirable to provide an epinephrine formulation for rapid delivery, including without the need for injecting the drug, such as by an intranasal route or by oral mucosal absorption.

[0058] In accordance with a first aspect, there is provided a formulation comprising acetyl cysteine and epinephrine. In preferred embodiments, the formulation is a liquid formulation. In some embodiments, the formulation is a solution. In some embodiments, the acetyl cysteine forms a salt with the epinephrine. In some embodiments, the acetyl cysteine forms a hydrogen bond with the epinephrine.

[0059] In a second aspect there is provided the formulation of the first aspect for use in therapy.

[0060] In a third aspect, there is provided a method of treatment of a disease, wherein the disease is associated with hypersensitivity reactions and / or wherein the disease is selected from cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the formulation of the first aspect.

[0061] In a fourth aspect, there is also provided a liquid buccal formulation comprising a formulation according to the first aspect of the invention.

[0062] In a fifth aspect, there is provided a method of delivering a liquid formulation to the oral cavity of a subject, the method comprising administering to the oral cavity a liquid buccal formulation according to the fourth aspect. The method typically comprises delivering a sufficient volume of liquid formulation in the sublingual or vestibular space. This enables direct contact of the liquid formulation with the oral mucosal membrane to promote adequate absorption of the pharmacologically active basic compound by the buccal route. Typically, the formulation is administered between the gum and the cheek (i.e., inner lining of the cheek), which may otherwise be referred to as the buccal pouch. The buccal pouch may be in a human subject. However, in some embodiments and in some test subjects (e.g., rats), the formulation may be administered under the tongue.

[0063] In various embodiments, formulations of a desired stability, especially in comparison with other formulations comprising epinephrine on the market, are provided. For example, the formulations disclosed herein return a high recovery of the undegraded pharmacologically active epinephrine drug. Minimal changes in chiral purity are also often observed. The formulation has a longer shelf-life than other epinephrine formulations.

[0064] In various embodiments, formulations having a desirable high water and / or aqueous solubility, especially at or near neutral pH. This is not possible with the acid salts (i.e., HC1 or bitartrate) used in prior formulations, which instead require lowering of the pH substantially. The present formulations can therefore be formulated at a higher nearer-neutral pH (e.g., pH > 4.5) than compared with existing marketed formulations of epinephrine. This has the advantage that a wide variety of administration routes are possible, including intravenous injection (e.g., intramuscular injection), nasal, oral, ophthalmic or other routes of administration.

[0065] In various embodiments, formulations provided herein have a desired stability and / or solubility of epinephrine, leading to the availability of to a higher wt.% of epinephrine in the formulations as compared to existing marketed formulations. The dosage volume of the formulations disclosed herein may therefore be less for equivalent doses of epinephrine from other marketed formulations of the drug. For administration from autoinjector devices or with other injection devices intended for rapid administration, a lower dose volume enables a quicker and more complete injection in less time reducing the likelihood of underdosing. Good stability in the absence of sodium metabisulfite. This is advantageous and improved over sulfite- containing formulations, since the formulation is suitable for those that are sensitive to sulfites, desired absence of sulfites, sulfates, chelators / chelants and common antioxidants such as ascorbic acid, vitamin A, vitamin E, propylgallate, ascorbyl palmitate, butylated hydroxytoluene (BHT), citric acid, alkyl gallates, gallic acid, where such ingredients can cause an adverse effect or a safety risk for infants and children or susceptible patients.

[0066] In various embodiments, provided herein are formulations having desired suitability of the formulation for buccal administration, i.e., suitable for buccal delivery to the sublingual and / or oral vestibular space between the cheeks and the gums. Without wishing to be bound by theory, this is considered to be achievable due to the mucolytic properties of, for example, acetyl cysteine and the low dosage volume of the epinephrine.

[0067] In various embodiments, the buccal formulations provided herein have a pleasant taste. This may be achieved, in part, by the presence of a sweetener, which can reduce any sharp or bitter taste, thereby reducing the salivary response to the formulation.

[0068] In various embodiments, buccal formulations provide a desired delivery, that can, inve some embodiments, be aided by the hypotonic osmolality of certain formulations, which improves buccal delivery by triggering higher fluid uptake into the epithelial cells.

[0069] The details, examples and preferences provided in relation to any particular one or more of the stated aspects of the present invention apply equally to all aspects of the present invention. Any combination of the embodiments, examples and preferences described herein in all possiblevariations thereof is encompassed by the present invention unless otherwise indicated herein, or otherwise clearly contradicted by context.DETAILED DESCRIPTION

[0070] The present inventors surprisingly found that a combination of acetyl cysteine and epinephrine led to formulations with good stability that were suitable for rapid absorption, for example, through the intranasal and the oral mucosal membranes.

[0071] The formulations of acetyl cysteine and epinephrine disclosed herein can be present in salt form. The acetyl cysteine may form a salt with epinephrine, which may happen in-situ or in solution. In some embodiments, the acetyl cysteine can additionally or alternatively form a hydrogen bond with the epinephrine.

[0072] The conjugate acid of the basic compound may have a pKa of 8 or higher, or a pKa of 9 or higher. The basic compound may comprise an amine group. The amine group may be a secondary amine group. The amine group may be directly attached or attached via a linker (e.g., a substituted or unsubstituted alkyl chain) to an aromatic ring substituted with one or more hydroxyl groups. The amine group may be directly attached or attached via a linker (e.g., a substituted or unsubstituted alkyl chain) to epinephrine.

[0073] The formulations described herein may be in any suitable form, for example, the formulation may exist either as a liquid solution or a solid-phase mixture of its constituents (i.e., at the temperature of storage). In preferred embodiments and examples, the formulation is a liquid formulation (i.e., the formulation is a liquid solution). In some embodiments, the formulation is a liquid solution suitable for injection (e.g., intravenous and more particularly intramuscular injection), nasal, oral, ophthalmic or buccal delivery. In some embodiments, the formulation is formulated in a dosage volume which is less than 0.5 mL, preferably less than 0.2 mL, preferably less than 0.1 mL, and even more preferably less than 0.075 mL. The improved stability and solubility of the pharmacologically active basic compound, aided by acetyl cysteine, enables a lower dosage volume.

[0074] The formulations described herein may have any suitable osmolality. In some embodiments, the tonicity of the formulation is about 100 mOsm / kg to about 450 mOsm / kg. In some embodiments, the formulation is hypotonic. In some embodiments, the tonicity of the formulation is about 120 mOsm / kg to about 250 mOsm / kg, or from about 150 mOsm / kg to about 250 mOsm / kg, or from about 175 mOsm / kg to about 225 mOsm / kg, or from about 180 mOsm / kg to about 220 mOsm / kg, or about 200 mOsm / kg. In some embodiments, the tonicity is greater than about 100 mOsm / kg, or greater than about 150 mOsm / kg, or greater than about 175 mOsm / kg, or greater than or equal to about 200 mOsm / kg. In some embodiments, the tonicity isless than about 450 mOsm / kg, or less than about 400 mOsm / kg, or less than about 350 mOsm / kg, or less than about 300 mOsm / kg, or less than about 250 mOsm / kg, or less than about 225 mOsm / kg, or less than or equal to about 200 mOsm / kg. In some embodiments, the formulation is formulated as an intravenous solution or a buccal solution.

[0075] The formulation described herein may have any suitable pH. In some embodiments, the pH may be between 3 and 8. In some embodiments, the pH may be greater than 4.5, or greater than 5. A near- neural pH enables the formulation to be delivered by a wide range of administration methods. In some embodiments, the pH of the formulation is between 4.5 and 7. In some embodiments, the pH of the formulation is between 5 and 6, or between 5 and 5.5.

[0076] The term “formulation” as used herein can also be replaced by, or used interchangeably with, the term “pharmaceutical formulation”. The disclosure in reference to the formulation also applies to the formulation for use in therapy, the method of treating a disease, the method of delivering a liquid formulation to the buccal cells and liquid buccal formulation and the liquid buccal formulation disclosed herein.

[0077] All amounts provided at a wt.% in relation to the formulation refers to the weight percent based on the total weight of the formulation.Epinephrine

[0078] Epinephrine is also known as adrenaline. Epinephrine has the following structure.

[0079] Epinephrine is intended to encompass both the pharmacologically active L- and inactive D- isomers, both the free acid and salt form of epinephrine, along with epinephrine analogues or derivatives.

[0080] In some embodiments, the formulation comprises the L-epinephrine in salt form, such as, wherein the acetyl cysteine forms a salt with the epinephrine (e.g., in-situ or in solution). This may be referred to as the acetyl cysteinate salt of epinephrine. Additionally or alternatively, the acetyl cysteine may form a hydrogen bond with the epinephrine.

[0081] The formulation may comprise any suitable amount of epinephrine. In some embodiments, the formulation comprises or is prepared using about from 0.001 wt.% to about 50wt.% of epinephrine. In some embodiments, the formulation comprises or is prepared using from about 0.01 wt.% to about 2.5 wt.% epinephrine, or from about 0.05 wt.% to about 2 wt.% epinephrine, or from about 0.1 wt.% to about 1 wt.% epinephrine, or between about 0.25 wt.% to about 0.75 wt.% epinephrine. In some embodiments, the formulation comprises greater than about 0.001 wt.% epinephrine (e.g., from about 0.001 wt.% to about 2.5 wt.%), or greater than about 0.01 wt.% epinephrine (from e.g., about 0.01 wt.% to about 2.5 wt.%), or greater than about 0.05 wt.% epinephrine (e.g., from about 0.05 wt.% to about 2.5 wt.%), or greater than about 0.1 wt.% epinephrine (e.g., from about 0.05 wt.% to about 1 wt.%), or greater than about 0.25 wt.% epinephrine (e.g., from about 0.25 wt.% to about 1 wt.%), or greater than about 0.35 wt.% epinephrine (e.g., from about 0.35 wt.% to about 1 wt.%), or greater than about 0.4 wt.% epinephrine (e.g., from about 0.4 wt.% to about 1 wt.%), or greater than about 0.45 wt.% epinephrine (e.g., from about 0.45 wt.% to about 1 wt.%), or greater than or equal to about 0.5 wt.% epinephrine (e.g., from about 0.5 wt.% to about 1 wt.%). In some embodiments, the formulation comprises less than about 50 wt.% epinephrine (e.g., from about 0.05 wt.% to about 50 wt.%), or less than about 25 wt.% epinephrine (e.g., from about 0.05 wt.% to about 25 wt.%), or less than about 10 wt.% epinephrine (e.g., from about 0.05 wt.% to about 10 wt.%), or less than about 5 wt.% epinephrine (e.g., from about 0.05 wt.% to about 5 wt.%), or less than about 2.5 wt.% epinephrine (e.g., from about 0.1 wt.% to about 2.5 wt.%), or less than about 2 wt.% epinephrine (e.g., from about 0.1 wt.% to about 2 wt.%), or less than about 1.5 wt.% epinephrine (e.g., from about 0.1 wt.% to about 1.5 wt.%), or less than about 1 wt.% epinephrine (e.g., from about 0.1 wt.% to about 1 wt.%), or less than about 0.75 wt.% epinephrine (e.g., from about 0.1 wt.% to about 0.75 wt.%), or less than about 0.6 wt.% epinephrine (e.g., from about 0.1 wt.% to about 0.6 wt.%). In some embodiments, the epinephrine is a pro-drug of epinephrine.

[0082] In some embodiments, the amount or concentration of epinephrine in solution is greater than about 2.5 mg / mL, or greater than about 3 mg / mL, or greater than about 4 mg / mL, or greater than or equal to about 5 mg / mL.Acetylcysteine

[0083] The formulations described herein comprise acetyl cysteine. Acetylcysteine may otherwise be referred to as N-acetylcysteine. In preferred embodiments, the acetyl-cysteine is N- acetyl-L-cysteine. As discussed above, acetyl cysteine is believed to stabilise and / or improve the solubility of epinephrine. In some embodiments, acetylcysteine is present in a molar excess of epinephrine. The mucolytic properties of acetylcysteine also means that the formulation is suitable for administration via buccal delivery or nasal deliver}', among the other administration routes described elsewhere herein.

[0084] For example, N-acetyl-L-cysteine (NAC) is the N-acetylated derivative of the natural amino acid L-cysteine and has been reportedly effective as an anti-infective agent, as an antioxidant, as a free radical scavenger, and is approved by the FDA for use as a mucolytic, as well as an antidote to acetaminophen poisoning. NAC acts as a source of cysteine to replenish the reserves of glutathione in the liver for the neutralization of toxic metabolites of acetaminophen that could otherwise accumulate in the liver, especially after an overdose of the drug. The carboxylic acid group of NAC with a pKa of about 3.2, is ionized at neutral pH, as N- acetyl-L-cysteinate ions. The thiol (-SH) or the sulfahydryl group in NAC, which is responsible for crosslinking and disrupting the mucus barrier, is basic (pKa around 9.5) and tends to be partially ionized with a positive charge at neutral pH. Solutions of NAC in water tend to be quite acidic (pH <3), but it tends to be poorly soluble at or near neutral pH. For similar reasons, many nonpolar basic drugs with a pKa close to neutral pH may be inadequately ionized and have poor solubility in physiological media.

[0085] In some examples, it was surprisingly found by the present inventors that a combination of NAC with a poorly soluble basic drug, such as epinephrine, has sufficiently high solubility for both entities at or near neutral pH (7.0). Even more surprisingly, the combination of the free base epinephrine and NAC in solution, when administered sublingually to rats, results in rapid absorption in contrast to the poor oral bioavailabilty of epinephrine. After sublingual administration of the liquid solution, epinephrine can be absorbed rapidly into the systemic circulation reaching peak plasma levels in about lOminutes. Currently, many sublingual and buccal drugs are formulated in the solid phase, either as buccal tablets or oral films. Yet, the novel solution formulation cited here also results in surprisingly high absorption through mucosal barrier and oral epithelium. NAC and epinephrine form a stable solution phase, such that the chemical and physical stability, is markedly improved. Using this combination, epinephrine, which is susceptible to oxidation, can be formulated as a high concentration solution at or near neutral pH with comparable or better stability to many marketed products containing the hydrochloride or other acid salts of epinephrine, even without added antioxidants.

[0086] The formulation may comprise any suitable amount of acetylcysteine. In some embodiments, the formulation comprises or is prepared using from about 0.001 wt.% to about 50 wt.% acetylcysteine. In some embodiments, the formulation comprises or is prepared using from about 0.1 wt.% to about 2.5 wt.% acetylcysteine, or from about 0.25 wt.% to about 2.5 wt.% acetylcysteine, or from about 0.5 wt.% to about 2.25 wt.% acetylcysteine, or from about 1.25 wt.% to about 2 wt.% acetylcysteine, or from about 1.35 wt.% to about 1.9 wt.% acetylcysteine, or from about 1.5 wt. % to about 1.8 wt.% acetylcysteine.

[0087] In some embodiments, the formulation comprises greater than about 0.001 wt.% acetylcysteine (e.g., from about 0.001 wt.% to about 2.5 wt.%), or greater than about 0.01 wt.% acetylcysteine (from e.g., about 0.01 wt.% to about 2.5 wt.%), or greater than about 0.05 wt.% acetylcysteine (e.g., from about 0.05 wt.% to about 2.5 wt.%), or greater than about 0.1 wt.% acetylcysteine (e.g., from about 0.1 wt.% to about 2.5 wt.%), or greater than about 0.25 wt.% acetylcysteine (e.g., from about 0.25 wt.% to about 2.5 wt.%), or greater than about 0.5 wt.% acetylcysteine (e.g., from about 0.5 wt.% to about 2.5 wt.%), or greater than about 0.75 wt.% acetylcysteine (e.g., from about 0.75 wt.% to about 2.5 wt.%), or greater than about 1 wt.% acetylcysteine (e.g., from about 1 wt.% to about 2.5 wt.%), or greater than about 1.2 wt.% acetylcysteine (e.g., from about 1.2 wt.% to about 2.5 wt.%), or greater than about 1.3 wt.% acetylcysteine (e.g., from about 1.3 wt.% to about 2.5 wt.%), or greater than about 1.4 wt.% acetylcysteine (e.g., from about 1.4 wt.% to about 2.5 wt.%), or greater than about 1.5 wt.% acetylcysteine (e.g., from about 1.5 wt.% to about 2.5 wt.%). In some embodiments, the formulation comprises less than about 50 wt.% acetylcysteine (e.g., from about 0.05 wt.% to about 50 wt.%), or less than about 25 wt.% epinephrine (e.g., from about 0.05 wt.% to about 25 wt.%), or less than about 10 wt.% acetylcysteine (e.g., from about 0.05 wt.% to about 10 wt.%), or less than about 5 wt.% acetylcysteine (e.g., from about 0.05 wt.% to about 5 wt.%), or less than about 2.5 wt.% acetylcysteine (e.g., from about 0.1 wt.% to about 2.5 wt.%), or less than about 2 wt.% acetylcysteine (e.g., from about 0.1 wt.% to about 2 wt.%).Other Components

[0088] In some embodiments, the formulation further comprises arginine, such as L-arginine. In some embodiments, the formulation may comprise or may be prepared using up to about 1.5 wt.% arginine, or up to about 1 wt.% arginine. In some embodiments, the formulation comprises or is prepared using from about 0.01 wt.% to about 1.5 wt.% arginine. In some embodiments, the formulation comprises or is prepared using from about 0.05 wt.% to about 1.5 wt.% arginine, or from about 0.05 wt.% to about 1 wt.% arginine, or from about 0.075 wt.% to about 0.75 wt.% arginine, or from about 0.1 wt.% to about 0.5 wt.% arginine, or from about 0.15 wt.% to about 0.4 wt.% arginine, or from about 0.2 wt.% to about 0.3 wt.% arginine.

[0089] In some embodiments, the formulation comprises greater than about 0.01 wt.% arginine (e.g., from about 0.01 wt.% to about 1.5 wt.%), or greater than about 0.05 wt.% arginine (from e.g., about 0.05 wt.% to about 1.5 wt.%), or greater than about 0.1 wt.% arginine (e.g., from about 0.1 wt.% to about 1.5 wt.%), or greater than about 0.2 wt.% arginine (e.g., from about 0.2 wt.% to about 1.5 wt. %). In some embodiments, the formulation comprises less than about 1.5 wt.% arginine (e.g., from about 0.05 wt.% to about 1.5 wt.%), or less than about 1 wt.% arginine(e.g., from about 0.05 wt.% to about 1 wt.%), or less than about 0.75 wt.% arginine (e.g., from about 0.05 wt.% to about 0.75 wt.%), or less than about 0.5 wt.% arginine (e.g., from about 0.05 wt.% to about 0.5 wt.%), or less than about 0.3 wt.% arginine (e.g., from about 0.1 wt.% to about 0.3 wt.%). In some embodiments, the arginine is added to the formulation as a high-purity arginine. In some embodiments, the high purity arginine may have a purity > 98%, preferably > 99%, and more preferably greater than 99.5%. In some embodiments, the formulations comprising arginine was seen to further improve the stability and solubility of the formulation.

[0090] In some embodiments, the formulation may further comprise an alkali bicarbonate, such as sodium bicarbonate. In some embodiments, the formulation may further comprise or be prepared using up to about 2 wt.% sodium bicarbonate, or up to about 1 wt.% sodium bicarbonate, or up to about 0.75 wt.% sodium bicarbonate. In some embodiments, the formulation may further comprise or be prepared using from about 0.1 wt.% to about 1 wt.% sodium bicarbonate, or from about 0.2 wt.% to about 0.7 wt.% sodium bicarbonate.

[0091] In some embodiments, the formulations comprising sodium bicarbonate may contribute to the increased pH of the formulation as compared to existing marketed formulations of epinephrine.

[0092] In some embodiments, the formulation may further comprise a sweetener. In some embodiments, the sweetener may be selected from saccharin, a saccharin salt, a sugar alcohol, a monosaccharide sugar or a disaccharide sugar, optionally wherein the sweetener is selected from sucralose, xylitol, sucrose, mannitol, fructose and sodium saccharin. In some embodiments, the sweetener is saccharin or a saccharin salt, which may be in hydrated or anhydrous form. In some embodiments, the sweetener is a sodium salt. In some embodiments, the formulation may comprise up to about 2 wt.% sweetener, or up to about 0.5 wt.% of sweetener, or up to about 0.1 wt.% of sweetener, or up to about 0.075 wt.% sweetener. In some embodiments, wherein the sweetener is saccharin or s saccharin salt, the formulation may comprise between about 0.01 wt.% to about 1 wt.% sweetener, and in some embodiments, between about 0.02 wt.% to about 0.06 wt.% sweetener.

[0093] In some embodiments, the formulation may further comprise cysteine or any cysteine salt. In some embodiments, the cysteine is L-cysteine. The cysteine or cysteine salt may be in hydrated or anhydrous form. In some embodiments, the cysteine salt may be cysteine hydrochloride. In some embodiments, the formulation may comprise or may be prepared using up to about 1 wt.% cysteine or cysteine salt, or up to about 0.5 wt.% cysteine or cysteine salt, or up to about 0.25 wt.% cysteine or cysteine salt. In some embodiments, the formulation may comprise or may be prepared using from about 0.01 wt.% to about 0.2 wt.% cysteine or cysteinesalt.

[0094] In alternative embodiments, the formulation can be free of cysteine or a cysteine salt. In some embodiments, the formulation can comprise arginine but be free of cysteine or a cysteine salt. In alternative embodiments, the formulation can comprise cysteine or cysteine salt but can be free of arginine. In some embodiments, the formulation can comprise cysteine or a cysteine salt and arginine.

[0095] In some embodiments, the formulation is free of sulfates or sulfites, including sodium metabisulfite, sulfur dioxide, sodium sulfite, sodium bisulfite, potassium metabisulfite, calcium sulfite, calcium bisulfite and / or potassium bisulfite. In some embodiments, the formulation is free of all sulfate or sulfites, which may be advantageous for patients with sulfite allergies. In some embodiments, the formulation is free of any chelants or chelators. Chelants or chelators may include, but is not limited to, EDTA, DTPA, HEDTA, NTA.

[0096] In some embodiments, the formulation is free of one or more of ascorbic acid, vitamin A, vitamin E, propylgallate, ascorbyl palmitate, butylated hydroxytoluene (BHT), citric acid, alkyl gallates and gallic acid, and preferably free of any of ascorbic acid, vitamin A, vitamin E, propylgallate, ascorbyl palmitate, butylated hydroxytoluene (BHT), citric acid, alkyl gallates and gallic acid.

[0097] In some embodiments, the formulation comprises water (i.e., a balance of water). In some embodiments, the formulation comprises at least about 95 wt.% water, or at least about 96 wt.% water, for example, between about 95 wt.% to about 99 wt.% water.

[0098] In some embodiments, the formulation comprises a tonicity adjuster. The tonicity adjuster may be selected from sodium chloride, potassium chloride, mannitol, glycerin, glucose or dextrose, optionally wherein the tonicity adjuster is sodium chloride. In some embodiments, the tonicity of the formulation comprising a tonicity adjuster may be between about 250 and about 450 mOsm / kg, or between about 270 and about 320 mOsm / kg. In some embodiments, the formulation is free of a tonicity adjuster.

[0099] In some embodiments, the formulation is a liquid solution suitable for injection, nasal, oral, ophthalmic or buccal delivery.Liquid Buccal Formulations

[0100] Buccal delivery has many advantages over different administration routes. The buccal formulation is very easily administered, with no requirement for injection, thereby increasing patient compliance. The present invention, in various embodiments, provides a broad buccal delivery formulationfor a liquid formulation comprising acetylcysteine and epinephrine. Without being bound by theory it is considered that the presence of acetylcysteine as a mucolytic agentpromotes faster absorption by the buccal route. In some examples, the presence of acetylcysteine is found to improve the stability of epinephrine. This enables the epinephrine to be formulated at high concentration and lower dosage volumes, which improves the suitability of the formulation for buccal delivery. Amounts of acetylcysteine and preferred forms of acetylcysteine are as elsewhere described herein.

[0101] In some embodiments, the formulation is a liquid buccal formulation which is formulated and / or suitable for buccal delivery. The liquid buccal formulation is suitable for delivery to the sublingual and / or oral vestibular space. In preferred embodiments, the pharmacologically active amine is a epinephrine, as may be described elsewhere herein, and more particularly epinephrine. In preferred embodiments of the liquid buccal formulation, the liquid buccal formulation comprises a high concentration of epinephrine. The high concentration of epinephrine, may further improve the suitability of the formulation for buccal delivery.

[0102] In some embodiments, the amount of epinephrine in solution is greater than about 2.5 mg / mL, or greater than about 3 mg / mL, or greater than about 4 mg / mL or greater than or equal to about 5 mg / mL. The high concentration of epinephrine or other pharmacologically active basic compound enables smaller dosage volumes which are most suitable for buccal delivery. In some embodiments, the formulation is provided with a dosage volume of less than about 0.5 mL, or less than about 0.25 mL, or less than about 0.1 mL, or less than about 0.075 mL.

[0103] In some embodiments of the liquid buccal formulation, the liquid buccal formulation is hypotonic. This improves buccal delivery since a hypotonic solution triggers higher fluid uptake into the buccal cell. In some embodiments, the osmolality of the liquid buccal formulation is between about 120 and about 250 mOsm / kg, for example between about 150 and about 225 mOsm / kg, or from about 175 mOsm / kg to about 225 mOsm / kg, or from about 190 to about 210 mOsm / kg.

[0104] In preferred embodiments of the liquid buccal formulation, the formulation further comprises a sweetener. The amount and preferred forms of the sweetener may be as described elsewhere herein. The presence of a sweetener improves buccal delivery by reducing the salivary response caused by administration of the formulation (i.e., as compared to a formulation absent of sweetener).

[0105] The formulation may further comprise arginine, cysteine or cysteine salt, and / or sodium bicarbonate, and water as is described elsewhere herein.

[0106] The formulation may further be free of sulfites, sulfates, chelators or chelants, cysteine or cysteine salts, ascorbic acid, vitamin A, vitamin E, propylgallate, ascorbyl palmitate, butylated hydroxytoluene (BHT), citric acid, alkyl gallates or gallic acid, and a tonicity adjuster asdescribed elsewhere herein.

[0107] The formulation may, in various embodiments, be at neutral, or near neutral, pH. Exemplary Formulations

[0108] In some embodiments, the formulation comprises:

[0109] from about 1.25 wt.% to about 2 wt.% acetylcysteine, more preferably from about 1.5 wt.% to about 1.8 wt.% acetylcysteine, and from about 0.25 wt.% to about 1 wt.% epinephrine.

[0110] In some embodiments, the formulation comprises: from about 1.25 wt.% to about 2 wt.% acetylcysteine, from about 0.25 to about 0.75 wt.% epinephrine, up to about 1.5 wt.% arginine, up to about 2 wt.% sodium bicarbonate, and optionally up to about 2 wt.% sweetener.

[0111] In some embodiments, the formulation comprises: from about 1.5 wt.% to about 1.8 wt.% acetylcysteine, from about 0.25 to about 0.75 wt.% epinephrine, from about 0.1 wt.% to about 0.4 wt.% arginine, from about 0.25 wt.% to about 0.75 wt.% sodium bicarbonate, and optionally up to about 2 wt.% sweetener.

[0112] In some embodiments, the formulation comprises: from about 1.25 wt.% to about 2 wt.% acetylcysteine, more preferably from about 1.5 wt.% to about 1.8 wt.% acetylcysteine, from about 0.25 wt.% to about 1 wt.% epinephrine, up to about 1.5 wt.% arginine, preferably from about 0.1 wt.% to about 0.4 wt.% arginine, up to about 2 wt.% sodium bicarbonate, preferably about 0.25 wt.% to about 0.75 wt.% sodium bicarbonate, and optionally up to about 0.075 wt.% sweetener, optionally between about 0.02 wt.% to about 0.06 wt.% sweetener.

[0113] In some embodiments, the formulation comprises: about 1.25 wt.% to about 2 wt.% acetylcysteine, more preferably from about 1.5 wt.% to about 1.8 wt.% acetylcysteine, from about 0.25 to about 1 wt.% epinephrine, up to about 1 wt.% cysteine or cysteine salt, preferably from about 0.01 wt.% to about 0.2 wt.% cysteine or cysteine salt, up to about 2 wt.% sodium bicarbonate, preferably from about 0.25 wt.% to about 0.75 wt.% sodium bicarbonate, and optionally up to about 0.075 wt.% sweetener, optionally between rom about 0.02 wt.% to about 0.06 wt.% sweetener.

[0114] In some embodiments, the formulation comprises: from about 1.25 wt.% to about 2 wt.% acetylcysteine, more preferably from about 1.5 wt.% to about 1.8 wt.% acetylcysteine, from about 0.25 to about 1 wt.% epinephrine, up to about 1.5 wt.% arginine, preferably from about 0.1 wt.% to about 0.4 wt.% arginine, up to about 1 wt.% cysteine or cysteine salt, preferably from about 0.01 wt.% to about 0.2 wt.% cysteine or cysteine salt, up to about 2 wt.% sodium bicarbonate, preferably from about 0.25 wt.% to about 0.75 wt.% sodium bicarbonate, and optionally up to about 0.075 wt.% sweetener, optionally between about 0.02 wt.% to about 0.06 wt.% sweetener.Uses and methods of treatment

[0115] Any formulation described herein may be used in therapy or as a medicament. This may be in accordance with the second aspect of the invention.

[0116] The formulations described herein also may be used in a method of treating a disease, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the formulations described herein, in various embodiments (e.g., the formulation described in the first aspect). Any formulation described herein may also be used in a method of treating a disease, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the formulation described herein (e.g., the formulation described in the first aspect).

[0117] In some embodiments, the disease is associated with hypersensitivity to allergic reactions and involves adrenergic receptor response. In some embodiments, the disease is associated with alpha adrenergic receptors or beta adrenergic receptors. In some embodiments, the disease is selected from cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the formulation of the first aspect.

[0118] The formulations may be administered using any suitable route. In some embodiments, the formulation is administered by injection (e.g., intravenous injection or intramuscular or subcutaneous injection). In some embodiments, the formulation is administered directly as drops or a spray into the nasal cavity. In some embodiments, the formulation is administered orally. In some embodiments, the formulation is administered topically into the conjunctival space in the eye or injected directly into the interior chambers of the eye, for example, intravitreally. In some embodiments, the formulation is administered via buccal delivery. In some embodiments, the formulation is administered via buccal delivery, where the solution is administered as drops or spray into the sublingual or vestibular spaces. Administering formulations described herein via buccal delivery, where the solution is administered as drops or spray into the sublingual or vestibular spaces, provides for absorption into systemic circulation taking place through the extensive vasculatory network underlying oral mucosal epithelium. Preferred embodiments for buccal delivery are described further below.

[0119] In some embodiments, the volume of formulation administered is less than about 0.5 mL, preferably less than about 0.25 mL, and in some embodiments less than about 0.1 mL, or less than about 0.075 mL. In some embodiments, the amount of epinephrine in solution is greater than about 2.5 mg / mL, or greater than about 3 mg / mL, or greater than about 4 mg / mL or greater than or equal to about 5 mg / mL.

[0120] In some embodiments of the medical uses and methods of treatment described herein, the subject is a human. In some embodiments, the subject is a livestock or equine species, or a companion animal, or is a test subject, for example, selected from a rat, mouse, any non-human primate (e.g., macaque, marmosets, tamarins, baboons and monkeys (inc. spider monkeys, owl monkeys, vervet monkeys, squirrel monkeys), mini or micro pig, guinea pig, rabbit, hamster, ferret, or dog.

[0121] Also described herein is a method of delivering a liquid formulation to the buccal cells of a subject, the method comprising administering to the oral cavity a liquid formulation comprising acetylcysteine and a pharmacologically effective amount of a basic pharmacologically active compound, namely epinephrine. The method typically comprises delivering a sufficient volume of liquid formulation in the sublingual or vestibular space either as one or more than one drop, or as a spray, such that there is immediate direct contact of the liquid formulation with the oral mucosal membrane to promote absorption of the pharmacologically active basic compound. Typically, the formulation is administered between the gum and the cheek (i.e., inner lining of the cheek or the oral vestibula space), e.g., in a human subject, which may otherwise be referred to as the buccal pouch. However, in some embodiments and in some test subjects (e.g., rats), the formulation may be administered under the tongue.

[0122] In some embodiments, the liquid formulation used in this method may be any suitable formulation described herein, but more preferably is in accordance with the liquid buccal formulation described herein. The method of delivery preferably comprises delivering the formulation to the sublingual and / or oral vestibular space.

[0123] In embodiments, the method of delivering the formulation may be used in a method of treating a disease associated with hypersensitivity reactions or severe allergic reactions. . In some embodiments, the disease is selected from cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup, wherein the method comprises administering to a subject in need thereof a therapeutically effective amount of the formulation of the first aspect.

[0124] In some embodiments of the method of delivery a formulation to the buccal cell described herein, the subject is a human. In some embodiments, the subject is a test subject, for example, selected from a rat, mouse, any non-human primate (e.g., macaque, marmosets, tamarins, baboons and monkeys (inc. spider monkeys, owl monkeys, vervet monkeys, squirrel monkeys), mini or micropig, guinea pig, rabbit, hamster, ferret, or dog.EXAMPLES:Example formulations:

[0126] The following formulations were prepared using standard methods and are free of chelators, sulfates sulfites or antioxidants.

[0127] Example 1 :The pH of Example 1 was 5.61.

[0128] Example 2:

[0129] The pH of Example 2 was 5.45. Example 2 is similar to Example 1 aside from the additional presence of saccharin. The presence of saccharin is considered to improve the suitability of the formulation, and administration of the formulation, for buccal delivery.

[0130] Example 3:

[0131] The pH of Example 3 was 5.94.

[0132] Example 4:

[0133] The pH of Example 4 was 4.65.

[0134] Example 5:

[0135] The pH of Example 5 was 6.82.

[0136] The above formulations provide many advantages over currently marketed formulations for epinephrine. Without wishing to be bound by theory, it is considered that the interaction between acetylcysteine and epinephrine, most likely due to formation of an acetylcysteinate salt of epinephrine, uniquely offers higher water solubility even at or nearer neutral pH. This is not possible with most acid salts (e.g., HC1 or bitartrate) that instead requires lowering of the pH substantially. This allows a wider variety of administration routes.

[0137] Current EPIPEN® Auto-Injectors contain 0.3 mg epinephrine in a 0.3 mL dose volume, along with 1.8 mg sodium chloride, 0.5 mg sodium metabisulfite, hydrochloric acid to adjust for pH and water for injection. Thus, as compared with these EPIPEN® formulations which have a formulation of Img / mL, epinephrine can instead be formulated at a concentration of ca. 5 mg / mL when formulated with N-acetylcysteine. At 5 x higher epinephrine concentration, the dose volume can be substantially reduced. As compared to the adult EPIPEN® dose volume of 0.3 mL, the formulation of the present invention can be administered with a 0.06 mL dose volume. This allows for a quicker and more complete injection (< Is) as compared to the at least 3 seconds required for EPIPEN®, since the slow administration of EPIPEN® often leads to underdosing.

[0138] The formulations described herein are also suitable for buccal delivery or buccal administration. Without wishing to be bound by theory, this is considered to be achievable due to the mucolytic activity of N-acetylcysteine which removes the viscous mucus layer that is an added barrier to the buccal epithelium.Stability Testing

[0139] Each of the above formulations were tested for epinephrine stability under thermal stress (40°C) up to 3 months. The stability was assessed using HPLC by both: (1) a chemical assay, which measured the relative peak area of the active compound, L-Epinephrine, over time, as well as (2) a chiral assay, which measured the relative percentage and the increase of the inactive D- enantiomer of epinephrine (i.e., (+)-epinephrine)).

[0140] Example 6

[0141] Example 7

[0142] Example s

[0143] Example 9

[0144] Example 10

[0145] Examples 6 to 10 comprise combinations of N-acetyl-L-cysteine and epinephrine. Surprisingly, these formulations demonstrated acceptable stability even in the absence of antioxidants and chelators.Rat Buccal Study

[0146] Five male Sprague Dawley® rats at about 6 to 8 weeks of age were administered 5 L of the test sample of the 5mg / mL solution formulation of L-epinephrine (Example 2) under the tongue. The precise dose was calculated based on the body weight of the animal. Plasma samples from the animals were collected at regular intervals and assayed for the active ingredient.Despite the extensive keratinization of the oral mucosa of the rats, epinephrine was rapidly absorbed and attained plasma levels commensurate with the dose. The table below shows the mean plasma epinephrine levels (± standard deviation) in 5 male rats following buccal dosing of formulation of epinephrine according to Example 7.

Claims

What is claimed is:

1. A buccal delivery formulation comprising a basic drug and an acidic compound with mucolytic properties.

2. The buccal delivery formulation of claim 1, wherein the acidic compound with mucolytic properties is an acetylcysteine.

3. The buccal delivery formulation of claim 2, wherein the acetylcysteine is selected from the group consisting of N-acetyl-L-cysteine, a structural analog thereof, or a derivative thereof.

4. The buccal delivery formulation of claim 1, wherein the basic drug has a pKa of 7.5 or higher.

5. The buccal delivery formulation of claim 1, wherein the basic drug has a conjugate acid of having a pKa of 8 or higher.

6. A buccal delivery formulation comprising N-acetyl-L-cysteine (NAC), or structural analogs or derivatives thereof, and a basic drug having a pKa of 7.5 or higher and a molecular weight of about 650 or less.

7. The buccal delivery formulation of claim 6, wherein the basic drug is selected from epinephrine, norepinephrine, dopamine, phenylephrine, a local anesthetic, lidocaine, bupivacaine, sildenafil, albuterol, amiodarone, amitriptyline, orphenadrine, fentanyl, ixazomib, sildenafil, sufentanil, tamoxifen, tofacitinib, toremifene, albuterol, abacavir, amphetamines, atropine, clopidogrel, ephedrine, Larotrectinib, morphine, neostigmine, phenelzine, rimegepant selumetinib, terbutaline, and tranylcypromine, and combinations thereof.

8. The buccal delivery formulation of claim 7, wherein the buccal delivery formulation is a liquid formulation.

9. The buccal delivery formulation of claim 8, wherein the liquid formulation is a solution.

10. The buccal delivery formulation of claim 2 or 8, wherein acetylcysteine is between about 0.001 wt.% to about 50 wt.% acetylcysteine, based on the total weight of the formulation.

11. The buccal delivery formulation of claim 10, wherein the acetylcysteine is N-acetyl-L-cysteine.

12. The buccal delivery formulation of claim 6, wherein the formulation comprises between about 0.01 wt.% and about 50 wt.% of the basic drug based on the total weight of the formulation.

13. The buccal delivery formulation of any one of the preceding claims, wherein the basic drug is epinephrine.

14. The buccal delivery formulation of any one of the preceding claims, wherein the acetylcysteine and the basic drug are present as salts.

15. The buccal delivery formulation of claim 2, wherein the amount of acetylcysteine is in molar excess of the basic drug.

16. The buccal delivery formulation of any one of the preceding claims, wherein the pH of the formulation is between 3 and 8.

17. The buccal delivery formulation of any one of the preceding claims comprising arginine in an amount of up to 1.5 wt.%, based on the total weight of the formulation.

18. The buccal delivery formulation of any one of the preceding claims comprising sodium bicarbonate in an amount of up to 2 wt.%, based on the total weight of the formulation.

19. The buccal delivery formulation of any one of the preceding claims further comprising a sweetener in an amount up to 2 wt.%, based on the total weight of the formulation.

20. The buccal delivery formulation of claim 19, wherein the sweetener is selected from the group consisting of saccharin, a saccharin salt, a sugar alcohol, a monosaccharide sugar, r a disaccharide sugar, and combinations thereof.

21. The buccal deliver formulation of claim 19, wherein the sweetener is selected from sucralose, xylitol, sucrose, mannitol, fructose, sodium saccharin, or combinations thereof.

22. The buccal delivery formulation of any one of the preceding claims comprising cysteine or a cysteine salt in an amount of up to 1 wt.% based of the total weight of the formulation.

23. The buccal delivery formulation of any one of claims 1 to 21, wherein the formulation is free of cysteine or a cysteine salt.

24. The buccal delivery formulation of any one of the preceding claims, wherein the formulation is free of chelants or chelators.

25. The buccal delivery formulation any one of the preceding claims, wherein the formulation is free of sulfates or sulfites.

26. The buccal delivery formulation of any one of the preceding claims, wherein the formulation is free of ascorbic acid, vitamin A, vitamin E, propylgallate, ascorbyl palmitate, butylated hydroxytoluene (BHT), citric acid, alkyl gallates, and gallic acid.

27. The buccal delivery formulation of any one of the preceding claims, comprising from about 1.25 wt.% to about 2 wt.% acetylcysteine, from about 0.25 to about 0.75 wt.% of the basic drug up to about 1.5 wt.% arginine, up to about 2 wt.% sodium bicarbonate, and optionally up to about 2 wt.% sweetener, wherein all wt.% are based on the total weight of the formulation.

28. The buccal delivery formulation of any one of claims 1 to 26, comprising from about 1.5 wt.% to about 1.8 wt.% acetylcysteine, from about 0.25 to about 0.75 wt.% of the basic drug, from about 0.1 wt.% to about 0.4 wt.% arginine, from about 0.25 wt.% to about 0.75 wt.% sodium bicarbonate, and optionally up to about 2 wt.% sweetener, wherein all wt.% are based on the total weight of the formulation.

29. The buccal delivery formulation of any one of the preceding claims, wherein the formulation is a liquid solution suitable for injection, nasal, oral, ophthalmic, or buccal delivery.

30. The buccal delivery formulation of any one of the preceding claims, wherein the tonicity of the formulation is from about 100 mOsm / kg to 450 mOsm / kg.

31. The buccal delivery formulation of any one of the preceding claims comprising a tonicity adjuster, and wherein the tonicity of the formulation to 270 mOsm / kg to 320mOsm / kg, and optionally wherein the tonicity adjuster is selected from sodium chloride, potassium chloride, mannitol, glycerin, glucose or dextrose, optionally wherein the tonicity adjuster is sodium chloride.

32. A method of treating a disease associated with hypersensitivity reactions, and / or wherein the disease is selected from cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup, comprising administering to a subject in need thereof a therapeutically effective amount of the buccal delivery formulation any one of the preceding claims 1 to 31.

33. The method of treating a disease of claim 32, wherein the dosage volume of the liquid formulation is less than 0.5.

34. The method of treating a disease of claim 32, wherein the amount of basic drug in solution is greater than 2.5 mg / mL.

35. The buccal delivery formulation of claim 1, wherein the formulation comprises a liquid buccal formulation.

36. The buccal delivery formulation of claim 34, wherein the liquid buccal formulation is hypotonic.

37. The buccal delivery formulationof claim 35, wherein the liquid buccal formulation has a tonicity of between about 120 and about 250 mOsm / kg.

38. The buccal delivery formulation of claim 35, wherein the liquid buccal formulation comprises a sweetener in an amount from 0.02 wt.% to 0.06 wt.%.

39. The buccal delivery formulation of claim 35, wherein the formulation is prepared using 0.01 wt.% to 2 wt.% acetylcysteine.

40. The buccal delivery formulation of claim 35, wherein the formulation is prepared using 0.25 to 0.75 wt.% of the basic drug.

41. The buccal delivery formulation of claim 35, wherein the formulation is formulated with a dosage volume of less than 0.5 mL.

42. A method of delivering a liquid formulation to the buccal cells of a subject, the method comprising administering to the oral cavity the buccal delivery formulation according to any one of claims 35 to 41.

43. The method of claim 42, wherein the formulation is delivered to the sublingual and / or oral vestibular space.

44. A method of delivering a liquid formulation to the buccal cells of a subject, comprising administering to the oral cavity the buccal delivery formulation according to any one of claims 35- 41.

45. The method of claim 32, wherein the formulation is delivered to the sublingual and / or oral vestibular space.

46. A method of treating a disease associated with hypersensitivity reactions comprising administering to a subject in need thereof a therapeutically effective amount of a buccal delivery formulation comprising acetylcysteine and a therapeutically effective amount of a basic drug.

47. A method of treating a disease selected from cardiac arrest, anaphylaxis, bronchiolitis, asthma or croup comprising administering to a subject in need thereof a therapeutically effective amount of a buccal delivery formulation comprising acetylcysteine and a therapeutically effective amount of a basic drug.

48. The method of claims 46 or 47, wherein acetylcysteine is N-acetyl-L-cysteine and the basic drug is epinephrine.

49. The method of claim 46, wherein the basic drug has a pKa of 7.5 or higher.

50. The method of claim 46, wherein the buccal delivery formulation comprising N-acetyl-L- cysteine (NAC), a structural analog of N-acetyl-L-cysteine, or derivatives thereof and a basic drug having a pKa of 7.5 or higher and a molecular weight of about 650 or less.

49. The method of claims 46 or 47, wherein the basic drug is selected from from epinephrine, norepinephrine, dopamine, phenylephrine, a local anesthetic, lidocaine, bupivacaine, sildenafil, albuterol, amiodarone, amitriptyline, orphenadrine, fentanyl, ixazomib, sildenafil, sufentanil, tamoxifen, tofacitinib, toremifene, albuterol, abacavir, amphetamines, atropine, clopidogrel, ephedrine, Larotrectinib, morphine, neostigmine, phenelzine, rimegepant selumetinib, terbutaline, and tranylcypromine, and combinations thereof.

50. A buccal delivery formulation for a basic drug comprising acetylcysteine.

51. The buccal delivery formulation of claim 50, wherein acetylcysteine is N-acetyl-L-cysteine, structural analogs, or derivatives thereof.

52. The buccal delivery formulation of claim 50, further comprises a basic drug.

53. The buccal delivery formulation of claim 52, wherein the basic drug has apKa of 7.5 or higher.

54. The buccal delivery formulation of claim 52, wherein the basic drug has a molecular weight of about 650 or less.

55. The buccal delivery formulation claim 51, wherein the acetylcysteine is N-acetyl-L-cysteine (NAC).