Sublingual formulations with water-soluble co-crystals of acetylsalicylic acid with citric acid, sodium bicarbonate and L-theanine for treatment of acute myocardial infarction

Abstract

The present invention relates to sublingual formulations having water-soluble co-crystals of acetylsalicylic acid with citric acid, sodium bicarbonate and L-theanine for the treatment of acute myocardial infarction. A water-soluble aspirin, citric acid, sodium bicarbonate, L-theanine eutectic composition is described, comprising an amount of acetylsalicylic acid. The composition may be produced by a process that includes different steps, including a co-crystallization step. The water soluble co-crystal composition is suitable for sublingual administration, preferably administration to a human.

Description

This application is a divisional application of the invention patent filed on May 30, 2018, with application number 201880050435.3, entitled "A sublingual preparation for treating acute myocardial infarction containing a water-soluble eutectic of acetylsalicylic acid, citric acid, sodium bicarbonate and L-theanine". Technical Field

[0001] This invention relates to a novel sublingual formulation for the treatment of acute myocardial infarction, using a water-soluble cocrystal product of acetylsalicylic acid, citric acid, sodium bicarbonate, and L-theanine. Background Technology

[0002] Heart disease remains a leading cause of death in the United States. Approximately 790,000 people experience a heart attack each year in the U.S. Of these, about 114,000 will die. The estimated annual incidence of heart attacks in the U.S. is 580,000 new attacks and 210,000 recurrent attacks. The average age at first heart attack is 65.3 years for men and 71.8 years for women. Approximately every 40 seconds, an American will experience a heart attack. Most out-of-hospital cardiac arrest (OHCA) occurs at home or residence (70%), with public places (19.8%) and nursing homes (10.6%) being the second and third most common locations for OHCA, respectively. Heart attack ($11.5 billion) and coronary artery disease ($10.4 billion) are two of the 10 most expensive primary hospital discharge diagnoses. Summary of the Invention

[0003] In one embodiment, the present invention relates to a composition comprising aspirin with citric acid, sodium bicarbonate, and L-theanine. In one embodiment, the present invention relates to a method for preparing a composition comprising aspirin with citric acid, sodium bicarbonate, and L-theanine. In some embodiments, the present invention relates to a cocrystal sublingual formulation of aspirin, citric acid, sodium bicarbonate, and L-theanine, wherein, compared to the conventional oral route of aspirin, the formulation can bypass the first-pass effect of the liver, exhibiting improved dissolution rate and bioavailability when rapid onset of action is required. In one embodiment, the present invention relates to a cocrystal sublingual formulation of aspirin, citric acid, sodium bicarbonate, and L-theanine, which is expected to significantly reduce median platelet aggregation inhibition time compared to the conventional oral route of aspirin. In one embodiment, the present invention relates to a water-soluble cocrystal product of acetylsalicylic acid with citric acid, sodium bicarbonate, and L-theanine for sublingual administration in the treatment of acute myocardial infarction.

[0004] In some embodiments, the present invention relates to cocrystal compositions of pharmaceuticals with enantiomers, L- and D-isomers, D,L-racemic mixtures, S- and R-isomers, S,R-racemic mixtures, all rotational isomers, tautomers, salt forms, and hydrates of theanine, wherein the N-substituted functional R1-group [C4 or γ-CH2-C(O)—NR1] may contain straight-chain, cyclic, or branched alkyl groups and their derivatives; straight-chain, cyclic, or branched alkenyl groups and their derivatives; and aromatic groups (which may be aryl groups) and their derivatives, constituting all analogous forms of theanine.

[0005] In some embodiments, the present invention relates to one or more of the following pharmaceutical preparations: Formulation #4 Formulation #5 Formulation #6 Formulation #7 All formulations had a disintegration time of less than 1 minute.

[0006] In one embodiment, this disclosure relates to a composition comprising aspirin, citric acid, sodium bicarbonate, and L-theanine. In some embodiments, the weight percentage of aspirin in the composition is between about 20% and about 30%. In some embodiments, the weight percentage of aspirin in the composition is selected from the group consisting of about 24.4%, about 25.0%, about 27.4%, and about 27.5%. In some embodiments, the weight percentage of L-theanine in the composition is between about 20% and about 30%. In some embodiments, the weight percentage of L-theanine in the composition is selected from the group consisting of about 24.6%, about 25.2%, about 27.7%, and about 27.8%. In some embodiments, the weight percentage of sodium bicarbonate in the composition is between about 15% and about 25%. In some embodiments, the weight percentage of sodium bicarbonate in the composition is selected from the group consisting of about 16.9%, about 17.4%, about 19.4%, and about 19.5%. In some embodiments, the weight percentage of citric acid in the composition is between about 5% and about 15%. In some embodiments, the weight percentage of citric acid in the composition is selected from the group consisting of about 8.8%, about 9.1%, about 9.6%, and about 9.7%. In some embodiments, the composition comprises one or more of a binder, emulsifier, and disintegrant. In some embodiments, the composition further comprises between about 2.5% and about 7.5% by weight of polyvinylpyrrolidone. In some embodiments, the weight percentage of polyvinylpyrrolidone in the composition is selected from the group consisting of about 4.8%, about 4.9%, and about 5.0%. In some embodiments, the polyvinylpyrrolidone is crosslinked. In some embodiments, the weight percentage of crosslinked polyvinylpyrrolidone in the composition is selected from the group consisting of about 3.1% and about 3.3%. In some embodiments, the composition further comprises a sugar alcohol. In some embodiments, the composition further comprises between about 5% and about 20.0% by weight of mannitol. In some embodiments, the mannitol in the composition is selected from the group consisting of about 7.4%, about 9.8%, about 16.5%, and about 17.9% by weight. In some embodiments, the composition further comprises a lubricant. In some embodiments, the composition further comprises magnesium stearate in weight percentages between about 0.01% and about 2.0%. In some embodiments, the magnesium stearate in the composition is about 0.5% by weight.

[0007] In one embodiment, this disclosure relates to a dosage form comprising aspirin, citric acid, sodium bicarbonate, and L-theanine. In some embodiments, the amount of aspirin in the dosage form is between about 300 mg and about 450 mg. In some embodiments, the amount of aspirin in the dosage form is selected from the group consisting of about 376 mg, about 379 mg, and about 381 mg. In some embodiments, the amount of L-theanine in the dosage form is between about 300 mg and about 450 mg. In some embodiments, the amount of L-theanine in the dosage form is selected from the group consisting of about 378 mg, about 379 mg, and about 383 mg. In some embodiments, the amount of sodium bicarbonate in the dosage form is between about 200 mg and about 350 mg. In some embodiments, the amount of sodium bicarbonate in the dosage form is selected from the group consisting of about 261 mg, about 264 mg, about 266 mg, and about 269 mg. In some embodiments, the dosage form contains citric acid in an amount between about 75 mg and about 200 mg. In some embodiments, the dosage form contains citric acid in an amount selected from the group consisting of about 131 mg, about 134 mg, about 136 mg, and about 137 mg. In some embodiments, the dosage form contains one or more of a binder, emulsifier, and disintegrant. In some embodiments, the dosage form further contains polyvinylpyrrolidone in an amount between about 50 mg and about 100 mg. In some embodiments, the dosage form contains polyvinylpyrrolidone in an amount selected from the group consisting of about 66 mg, about 69 mg, about 74 mg, and about 77 mg. In some embodiments, the polyvinylpyrrolidone is crosslinked. In some embodiments, the dosage form contains crosslinked polyvinylpyrrolidone in an amount between about 25 mg and about 75 mg. In some embodiments, the dosage form contains crosslinked polyvinylpyrrolidone in an amount selected from the group consisting of about 43 mg and about 52 mg. In some embodiments, the dosage form further includes a sugar alcohol. In some embodiments, the dosage form further comprises mannitol in an amount between about 50 mg and about 300 mg. In some embodiments, the amount of mannitol in the dosage form is selected from the group consisting of about 102 mg, about 135 mg, about 258 mg, and about 269 mg. In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the dosage form further comprises magnesium stearate in an amount between about 2.5 mg and about 15 mg. In some embodiments, the amount of magnesium stearate in the dosage form is selected from the group consisting of about 7.0 mg, about 7.5 mg, and about 8 mg.

[0008] In some embodiments, the present invention relates to a method for treating an acute myocardial infarction in a subject in need, the method comprising administering a sublingual aspirin cocrystal with citric acid, sodium bicarbonate, and L-theanine to the subject. In one embodiment, the sublingual aspirin, citric acid, sodium bicarbonate, and L-theanine cocrystal are directly absorbed in the bloodstream of the subject, bypassing the first-pass effect of the liver. Detailed Implementation Early administration of novel sublingual aspirin, citrate, sodium bicarbonate, and L-theanine cocrystal formulations for the treatment of acute myocardial infarction is crucial, and patients can begin to benefit within minutes, whereas the full benefits of conventional aspirin may not materialize until major sequelae (such as ventricular tachycardia, ventricular fibrillation, complete heart block, or death) occur. Therefore, there is a significant unmet need in patients with acute myocardial infarction for novel sublingual aspirin, citrate, sodium bicarbonate, and L-theanine cocrystal formulations with improved pharmacokinetics and pharmacodynamics. This invention addresses these and other medical needs and overcomes the deficiencies of the prior art.

[0009] Compared to the conventional oral route of aspirin, the advantages of the sublingual cocrystal of aspirin, citrate, sodium bicarbonate, and L-theanine include increased dissolution rate and bioavailability when rapid onset of action is required. The sublingual vascular network provides increased drug absorption compared to the oral route. Therefore, the sublingual vascular network results in a faster dissolution rate, especially if the saliva pH is greater than 6. The sublingual route bypasses the hepatic first-pass effect, leading to increased drug bioavailability because the drug is absorbed directly into the systemic circulation rather than through the gastrointestinal tract, where it is first delivered to the liver via the portal vein and then metabolized in the liver before entering the systemic circulation. Patients with a history of acute coronary syndrome can self-administer this cocrystal of aspirin, citrate, sodium bicarbonate, and L-theanine at home or at work before an ambulance arrives, while in the field, or during an acute episode of chest pain while traveling by air. Patients with a history of dysphagia (difficulty swallowing) or dysphagia (pain when swallowing) will benefit from the sublingual route.

[0010] A significant drawback of the sublingual route occurs in patients who smoke. Smokers will not fully benefit from the sublingual route because smoking causes vasoconstriction, which reduces drug absorption.

[0011] The ongoing interest in improving the physical properties of pharmaceutical substances has led to significant research into issues related to polymorphism and solvation morphology. Recently, it has been recognized that many substances can co-crystallize in a single continuous lattice structure, thus opening new avenues for pharmaceutical scientists to crystal engineering.

[0012] A eutectic is a mixed crystal, in which a eutectic is a homogeneous crystalline material formed from discrete, neutral molecules that are solid at ambient temperatures. A characteristic of a eutectic is that two or more molecules are associated at the molecular level but not bonded.

[0013] Cocrystals represent a new form of pharmaceutical substance that will be suitable for incorporation into solid dosage forms and should enable formulation scientists to overcome various problems encountered during the development of conventional formulations. Cocrystals can be considered as alternatives to polymorphs, solvatomorphs, and salts because they represent different approaches to addressing issues such as those related to dissolution, crystallinity, and hygroscopicity.

[0014] Eutectic crystals are attractive to the pharmaceutical industry because they offer the opportunity to alter the chemical and / or physical properties of APIs without the need to form or break covalent bonds.

[0015] Unfortunately, it is not yet possible to predict whether two substances will co-crystallize, and therefore co-crystallization screening studies are essentially empirical.

[0016] Given the structural similarity between glutamine and glutamic acid and theanine, and the fact that neither glutamine nor glutamic acid forms co-crystals with aspirin, one might have been led to infer that theanine would also not form co-crystals with aspirin. Despite this expectation, aspirin does indeed form co-crystals with theanine, but it does not form co-crystals with either glutamine or glutamic acid.

[0017] The conformational isomers described below are highly structurally related to L-theanine: Eutectic engineering can be used to improve one or more physical properties of a selected therapeutic or preventative active pharmaceutical ingredient, such as solubility, stability, and dissolution rate.

[0018] Salicylic acid is the active metabolite of aspirin.

[0019] Therapeutic compounds, such as aspirin, are most stable in their crystalline form, but may exhibit poor water solubility and a slow dissolution rate. These properties tend to reduce the bioavailability of the active pharmaceutical ingredient (API), thereby slowing absorption.

[0020] Myocardial infarction is most often caused by the rupture of atherosclerotic lesions in the coronary arteries. This rupture leads to the formation of a coronary thrombus or blood clot, which blocks the artery and prevents the artery from supplying blood and oxygen to the heart muscle, which is normally supplied by that vessel. As a result, ischemic death of myocardial cells occurs.

[0021] Activated macrophages and T lymphocytes at the plaque rupture site release metalloproteinases and cytokines, which weaken the fibrotic cap, making it susceptible to erosion or tearing due to shear stress exerted by blood flow. Plaque rupture exposes subendothelial collagen, a site of platelet adhesion, activation, and aggregation. This leads to the release of substances such as thromboxane A2, fibrinogen, serotonin, platelet-activating factor, and ADP (adenosine diphosphate), which further promotes platelet aggregation. Activation of the coagulation cascade leads to fibrin formation and the propagation of obstructive thrombi. When a thrombus forms on the ruptured plaque, it eventually obstructs the artery. Rupture of atherosclerotic plaques with superimposed thrombi accounts for 95% of acute myocardial infarction cases.

[0022] Inflammation and inflammatory cell infiltration are hallmarks of myocardial infarction and reperfusion injury. Ischemic cardiac injury activates the innate immune response via Toll-like receptors and upregulates the expression of chemokines and cytokines in the infarcted heart. The continuous infiltration of damaged myocardium by neutrophils, monocytes and their progeny macrophages, dendritic cells, and lymphocytes contributes to the initiation and resolution of inflammation, infarction healing, angiogenesis, and ventricular remodeling. The detrimental and beneficial effects in the pathophysiology of myocardial infarction (MI) and reperfusion injury may be attributed to the heterogeneity and functional diversity of these inflammatory cell subsets.

[0023] Aspirin irreversibly inhibits platelet cyclooxygenase 1 (COX-1) by acetylation of serine at amino acid position 529, thereby preventing arachidonic acid from entering the COX-1 catalytic site through steric hindrance. By inhibiting COX-1, platelets cannot synthesize prostaglandin H2, which is otherwise converted to thromboxane A2. Thromboxane A2 induces platelet aggregation, an early step in the coagulation cascade.

[0024] Theanine is found in green tea leaves (Camellia sinensis) and the non-edible mushroom *Xerocomus badius*, but is otherwise rare in nature. Tea is the second most consumed beverage in the world. Monks have been drinking tea containing theanine for over 4,000 years. L-Theanine is an ingredient in fruit juices and beverages, non-herbal teas, sports drinks, bottled water, chocolate bars, hard candies, mints, and chewing gum. Theanine is extremely safe, with an LD50 toxicity of >5000 mg / kg in rats. Based on the FDA's GRAS assessment of L-theanine (which is based on a statistical analysis of potential dietary intake), the estimated average theanine consumption is 682 mg / person / day, and the 90th percentile consumption is 1284 mg (1.28 g) / person / day.

[0025] L-Theanine (N-ethyl-L-glutamine) is an amino acid analog of glutamine and is a water-soluble non-protein amino acid. It is a tasteless, white crystalline powder, soluble in water, and transparent in solution. L-Theanine has Chemical Abstracts Service (CAS) registration number 3081-61-6 and GRAS classification (GRAS notification number: GRN000209). L-Theanine has the empirical formula C7H 14 N₂O₃ has a molecular weight of 174.20, a pKa of 2.35, and a melting point of 217-218℃. In the kidneys, glutaminase hydrolyzes theanine into glutamate and ethylamine.

[0026] Chemical structure of L-theanine Theanine is known to have several mechanisms of action. Thrombin is a serine protease that converts fibrinogen into fibrin during the coagulation cascade that leads to clot formation. Theanine itself is a potent inhibitor of thrombin-stimulated thromboxane preparations in whole blood. Therefore, theanine has an anticoagulant effect. This anticoagulant effect of theanine can be beneficial in the treatment of acute myocardial infarction when administered sublingually as a cocrystal of aspirin with citrate, sodium bicarbonate, and L-theanine. Theanine promotes the generation of alpha waves in the brain, inducing a relaxed mental and physical state without causing drowsiness. This relaxed mental and physical state would be beneficial in patients with acute myocardial infarction.

[0027] Theanine enhances the solubility of aspirin in water. As a 5-N-ethylglutamine, theanine differs from glutamine in that the CH2-CH3 (ethyl) group replaces the hydrogen. The N-ethyl group imparts its active properties to theanine. Theanine and its analogues form zwitterions at neutral pH. The ionic charge can be used to pair with the ortho-carboxylic acid anion of acetylsalicylic acid via cation or protonated α-amino groups. This can be further stabilized by hydrogen bonding with the nitrogen of the ethylcarboxamide (the acetylammonium is a functional marker of theanine-type molecules). Crystals of this ion pair can encapsulate more water molecules than either molecule alone. This makes the complex readily solubilized when dissolved in water or buffer solutions.

[0028] Aspirin protects against several types of toxicity, including excitotoxicity (glutamate), dopamine toxicity, and oxidative free radical toxicity.

[0029] Excitotoxicity is a pathological process responsible for neuronal cell death caused by excessive stimulation of neurotransmitters (such as glutamate). Pathologically, high levels of glutamate can cause neuronal cell death by allowing high levels of calcium ions (Ca). 2+ This calcium (Ca) enters cells and causes excitotoxicity. 2+The influx of theanine into cells leads to the release of multiple enzymes, resulting in neuronal death. It has been shown that theanine is related to AMPA (…). It binds to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, phycocyanin, NMDA (N-methyl-D-aspartate), and group 1mGluR receptors, thereby antagonizing excitatory neurotransmitters.

[0030] GABA (gamma-aminobutyric acid) is the most widespread inhibitory neurotransmitter in the brain. When GABA levels decrease, nerve impulses increase in neurons. Theanine increases GABA levels in the brain, counteracting the overstimulation of nerve impulses by excitatory neurotransmitters (such as glutamate), which can be found in patients with stroke and traumatic brain injury.

[0031] L-Theanine crosses the blood-brain barrier via a large, neutral amino acid-preferred transport system of leucine and has been shown to produce significant increases in serotonin and / or dopamine concentrations in the brain, primarily in the striatum, hypothalamus, and hippocampus. The ability of L-theanine to increase serotonin and dopamine concentrations in the brain will be beneficial in treating migraine patients where serotonin and dopamine levels are typically low.

[0032] A novel sublingual water-soluble cocrystal of aspirin, citric acid, sodium bicarbonate, and L-theanine, which crosses the blood-brain barrier, will have neuroprotective effects on a variety of central nervous system disorders associated with glutamate excitotoxicity, such as spinal cord injury, stroke, traumatic brain injury, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

[0033] Researchers at the Boyce Thompson Institute and Johns Hopkins University have discovered that salicylic acid, the active metabolite of aspirin, binds to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), preventing the enzyme from entering the neuronal nucleus, where it enhances protein turnover and leads to cell death. GAPDH is believed to play a crucial role in neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases. A novel sublingual water-soluble cocrystal of aspirin, along with citrate, sodium bicarbonate, and L-theanine, will be essential in preventing neuronal cell death by binding salicylic acid to glyceraldehyde-3-phosphate dehydrogenase.

[0034] Theanine inhibits the efflux of chemotherapeutic agents (such as doxorubicin, idarubicin, cisplatin, and irinotecan), leading to elevated drug levels in cancer cells, which strongly suppresses tumor growth. Theanine blocks the export of doxorubicin, idarubicin, cisplatin, and irinotecan from cancer cells by blocking the glutamate and glutathione transport mechanisms. Cancer cells use glutathione to counteract the toxicity of doxorubicin, idarubicin, cisplatin, and irinotecan and to deliver the drugs out of the cell. Theanine is able to interfere with this process due to its structural similarity to glutamate.

[0035] The various novel features characterizing the invention are specifically pointed out in the claims appended to and forming a part of this disclosure. For a better understanding of the invention, its operation, advantages, and specific objectives obtained through its use, reference is made to the descriptive content in which preferred embodiments of the invention are shown.

[0036] Therefore, one object of the present invention is to provide a method for using a cocrystal composition of aspirin with citric acid, sodium bicarbonate and L-theanine, said composition being readily administered to humans via the sublingual route, bypassing the first-pass effect of the liver, and improving dissolution rate and bioavailability.

[0037] Another object of the present invention is to provide a water-soluble aspirin, citric acid, sodium bicarbonate and theanine eutectic composition having the above-mentioned characteristics, and which is rapidly soluble in water.

[0038] Another object of the present invention is to provide a water-soluble cocrystal formulation of aspirin, citric acid, sodium bicarbonate, and theanine suitable for sublingual administration, having the above-mentioned characteristics and allowing acetylsalicylic acid to be rapidly delivered into the bloodstream.

[0039] Another object of the present invention is to provide a water-soluble cocrystal formulation of aspirin, citric acid, sodium bicarbonate, and theanine suitable for sublingual administration, having the above-mentioned characteristics and allowing for the rapid delivery of a therapeutic amount of theanine into the bloodstream.

[0040] A further object of the present invention is to provide a method for sublingual administration of a cocrystal composition of water-soluble aspirin, citric acid, sodium bicarbonate, and theanine in humans, said composition providing enhanced dissolution and bioavailability and being suitable for the treatment of acute myocardial infarction.

[0041] A further object of the present invention is to provide a water-soluble cocrystal composition of aspirin, citric acid, sodium bicarbonate, and theanine suitable for sublingual administration, which has the above-mentioned characteristics and is expected to reduce median platelet aggregation inhibition time compared with conventional oral aspirin.

[0042] A further object of the present invention is to provide a water-soluble cocrystal formulation of aspirin, citric acid, sodium bicarbonate, and theanine suitable for sublingual administration, having the above-mentioned characteristics and bypassing the gastrointestinal tract without causing gastrointestinal irritation, erosion, or bleeding that may occur with conventional oral aspirin use.

[0043] Embodiments of the present invention may include enantiomers, L- and D-isomers, D,L-racemic mixtures, S- and R-isomers, S,R-racemic mixtures, all rotational isomers, tautomers, salt forms, and hydrate cocrystal compositions of drugs of the kinds listed below with α and β amino acids of theanine, wherein the N-substituted functional R1-group [C4 or γ-CH2-C(O)—NR1] may contain straight-chain, cyclic, or branched alkyl groups and their derivatives; straight-chain, cyclic, or branched alkenyl groups and their derivatives; and aromatic groups (which may be aryl groups) and their derivatives, constituting all analogous forms of theanine.

[0044] In some embodiments of the invention, the theanine enantiomer further comprises a carbohydrate functional group thereon. In these embodiments, the carbohydrate functional group may have an L-configuration or a D-configuration. In these embodiments, the carbohydrate used may be a monosaccharide, disaccharide, trisaccharide, oligosaccharide, or polysaccharide.

[0045] In some embodiments of the invention, the theanine enantiomer further comprises an amino acid functional group thereon. In some of these embodiments, the amino acid functional group is a dipeptide.

[0046] Sodium bicarbonate is a white crystalline powder, highly soluble in water, with the molecular formula NaHCO3, CAS number 144-55-8, a molecular weight of 84.006 g / mol, and pKa values ​​of 6.4 and 10.3. Without being limited by the specific theory of this invention, sodium bicarbonate (NaHCO3) deprotonates the carboxylic acid of aspirin to produce sodium acetylsalicylate, which is more soluble in water due to the presence of the charged carboxylate group. Aspirin hydrolysis is pH-independent between 5 and 8, meaning that bicarbonate is a specific base catalyst for generating aspirin anions over a range up to saturation. The hydrolysis of aspirin acetate is pH-independent and depends only on the concentration of the aspirin carboxylate anion. At molar equivalents greater than 1.2, the extraction of a proton from the acid of aspirin is ultrafast and complete.

[0047] Citric acid, 2-hydroxypropane-1,2,3-tricarboxylic acid, CAS No. 77-92-9, has the molecular formula C6H8O7 and a molecular weight of 192.12 g / mol. It is readily soluble in water. It is a tribase with pKa values ​​of 5.21, 4.28, and 2.92 (1-3). Under physiological conditions, one of the acid groups is deprotonated, allowing the acid's conjugate base to bind to other molecules. Acidic citric acid dissolves calcium-based coagulants by chelating calcium out of clot complexes in the blood. Therefore, citrates have anticoagulant effects due to their ability to chelate calcium. This anticoagulant effect is beneficial in patients suffering from acute myocardial infarction when administered sublingually in the form of a cocrystal of aspirin, citric acid, sodium bicarbonate, and L-theanine. In formulations, citric acid reacts with sodium bicarbonate to produce a buffer, disintegrant, and favorable compressibility.

[0048] In one embodiment, this disclosure relates to a composition comprising aspirin, citric acid, sodium bicarbonate, and L-theanine. In some embodiments, the weight percentage of aspirin in the composition is between about 20% and about 30%. In some embodiments, the weight percentage of aspirin in the composition is selected from the group consisting of: about 20.00%, about 20.10%, about 20.20%, about 20.30%, about 20.40%, about 20.50%, about 20.60%, about 20.70%, about 20.80%, about 20.90%, about 21.00%, about 21.10%, about 21.20%, about 21.30%, about 21.40%, about 21.50%, about 21.60%, about 21.70%, about 21.80%, about 21.90%, about 22.00%, about 22.10%, about 2 2.20%, approximately 22.30%, approximately 22.40%, approximately 22.50%, approximately 22.60%, approximately 22.70%, approximately 22.80%, approximately 22.90%, approximately 23.00%, approximately 23.10%, approximately 23.20%, approximately 23.30%, approximately 23.40%, approximately 23.50%, approximately 23.60%, approximately 23.70%, approximately 23.80%, approximately 23.90%, approximately 24.00%, approximately 24.10%, approximately 24.20%, approximately 24.30%, approximately 24.40%, approximately 24.50%, approximately 24.60%, approximately 24.70%, approximately 24. 80%, approximately 24.90%, approximately 25.00%, approximately 25.10%, approximately 25.20%, approximately 25.30%, approximately 25.40%, approximately 25.50%, approximately 25.60%, approximately 25.70%, approximately 25.80%, approximately 25.90%, approximately 26.00%, approximately 26.10%, approximately 26.20%, approximately 26.30%, approximately 26.40%, approximately 26.50%, approximately 26.60%, approximately 26.70%, approximately 26.80%, approximately 26.90%, approximately 27.00%, approximately 27.10%, approximately 27.20%, approximately 27.30%, approximately 27.40% %, approximately 27.50%, approximately 27.60%, approximately 27.70%, approximately 27.80%, approximately 27.90%, approximately 28.00%, approximately 28.10%, approximately 28.20%, approximately 28.30%, approximately 28.40%, approximately 28.50%, approximately 28.60%, approximately 28.70%, approximately 28.80%, approximately 28.90%, approximately 29.00%, approximately 29.10%, approximately 29.20%, approximately 29.30%, approximately 29.40%, approximately 29.50%, approximately 29.60%, approximately 29.70%, approximately 29.80%, approximately 29.90%, and approximately 30.00%.

[0049] In some embodiments, the weight percentage of L-theanine in the composition is between about 20% and about 30%. In some embodiments, the weight percentage of L-theanine in the composition is selected from the group consisting of: about 20.00%, about 20.10%, about 20.20%, about 20.30%, about 20.40%, about 20.50%, about 20.60%, about 20.70%, about 20.80%, about 20.90%, about 21.00%, about 21.10%, about 21.20%, about 21.30%, about 21.40%, about 21.50%, about 21.60%, about 21.70%, about 21.80%, about 21.90%, about 22.00%, about 22.10%, about... 22.20%, approximately 22.30%, approximately 22.40%, approximately 22.50%, approximately 22.60%, approximately 22.70%, approximately 22.80%, approximately 22.90%, approximately 23.00%, approximately 23.10%, approximately 23.20%, approximately 23.30%, approximately 23.40%, approximately 23.50%, approximately 23.60%, approximately 23.70%, approximately 23.80%, approximately 23.90%, approximately 24.00%, approximately 24.10%, approximately 24.20%, approximately 24.30%, approximately 24.40%, approximately 24.50%, approximately 24.60%, approximately 24.70%, approximately 24 0.80%, approximately 24.90%, approximately 25.00%, approximately 25.10%, approximately 25.20%, approximately 25.30%, approximately 25.40%, approximately 25.50%, approximately 25.60%, approximately 25.70%, approximately 25.80%, approximately 25.90%, approximately 26.00%, approximately 26.10%, approximately 26.20%, approximately 26.30%, approximately 26.40%, approximately 26.50%, approximately 26.60%, approximately 26.70%, approximately 26.80%, approximately 26.90%, approximately 27.00%, approximately 27.10%, approximately 27.20%, approximately 27.30%, approximately 27.4 0%, approximately 27.50%, approximately 27.60%, approximately 27.70%, approximately 27.80%, approximately 27.90%, approximately 28.00%, approximately 28.10%, approximately 28.20%, approximately 28.30%, approximately 28.40%, approximately 28.50%, approximately 28.60%, approximately 28.70%, approximately 28.80%, approximately 28.90%, approximately 29.00%, approximately 29.10%, approximately 29.20%, approximately 29.30%, approximately 29.40%, approximately 29.50%, approximately 29.60%, approximately 29.70%, approximately 29.80%, approximately 29.90%, and approximately 30.00%.

[0050] In some embodiments, the weight percentage of sodium bicarbonate in the composition is between about 15% and about 25%. In some embodiments, the weight percentage of sodium bicarbonate in the composition is selected from the group consisting of: about 15.00%, about 15.10%, about 15.20%, about 15.30%, about 15.40%, about 15.50%, about 15.60%, about 15.70%, about 15.80%, about 15.90%, about 16.00%, about 16.10%, about 16.20%, about 16.30%, about 16.40%, about 16.50%, about 16.60%, about 16.70%, about 16.80%, about 16.90%, about 17.00%, about 17.10%, about 1 7.20%, approximately 17.30%, approximately 17.40%, approximately 17.50%, approximately 17.60%, approximately 17.70%, approximately 17.80%, approximately 17.90%, approximately 18.00%, approximately 18.10%, approximately 18.20%, approximately 18.30%, approximately 18.40%, approximately 18.50%, approximately 18.60%, approximately 18.70%, approximately 18.80%, approximately 18.90%, approximately 19.00%, approximately 19.10%, approximately 19.20%, approximately 19.30%, approximately 19.40%, approximately 19.50%, approximately 19.60%, approximately 19.70%, approximately 19. 80%, approximately 19.90%, approximately 20.00%, approximately 20.10%, approximately 20.20%, approximately 20.30%, approximately 20.40%, approximately 20.50%, approximately 20.60%, approximately 20.70%, approximately 20.80%, approximately 20.90%, approximately 21.00%, approximately 21.10%, approximately 21.20%, approximately 21.30%, approximately 21.40%, approximately 21.50%, approximately 21.60%, approximately 21.70%, approximately 21.80%, approximately 21.90%, approximately 22.00%, approximately 22.10%, approximately 22.20%, approximately 22.30%, approximately 22.40% %, approximately 22.50%, approximately 22.60%, approximately 22.70%, approximately 22.80%, approximately 22.90%, approximately 23.00%, approximately 23.10%, approximately 23.20%, approximately 23.30%, approximately 23.40%, approximately 23.50%, approximately 23.60%, approximately 23.70%, approximately 23.80%, approximately 23.90%, approximately 24.00%, approximately 24.10%, approximately 24.20%, approximately 24.30%, approximately 24.40%, approximately 24.50%, approximately 24.60%, approximately 24.70%, approximately 24.80%, approximately 24.90%, and approximately 25.00%.

[0051] In some embodiments, the weight percentage of citric acid in the composition is between about 5% and about 15%. In some embodiments, the weight percentage of citric acid in the composition is selected from the group consisting of: about 5.00%, about 5.10%, about 5.20%, about 5.30%, about 5.40%, about 5.50%, about 5.60%, about 5.70%, about 5.80%, about 5.90%, about 6.00%, about 6.10%, about 6.20%, about 6.30%, about 6.40%, about 6.50%, about 6.60%, about 6.70%, about 6.80%, about 6.90%, about 7.00%, about 7.10%, about 7.20%, and about 7.30%. Approximately 7.40%, approximately 7.50%, approximately 7.60%, approximately 7.70%, approximately 7.80%, approximately 7.90%, approximately 8.00%, approximately 8.10%, approximately 8.20%, approximately 8.30%, approximately 8.40%, approximately 8.50%, approximately 8.60%, approximately 8.70%, approximately 8.80%, approximately 8.90%, approximately 9.00%, approximately 9.10%, approximately 9.20%, approximately 9.30%, approximately 9.40%, approximately 9.50%, approximately 9.60%, approximately 9.70%, approximately 9.80%, approximately 9.90%, approximately 10.00%, approximately 10.10% %, approximately 10.20%, approximately 10.30%, approximately 10.40%, approximately 10.50%, approximately 10.60%, approximately 10.70%, approximately 10.80%, approximately 10.90%, approximately 11.00%, approximately 11.10%, approximately 11.20%, approximately 11.30%, approximately 11.40%, approximately 11.50%, approximately 11.60%, approximately 11.70%, approximately 11.80%, approximately 11.90%, approximately 12.00%, approximately 12.10%, approximately 12.20%, approximately 12.30%, approximately 12.40%, approximately 12.50%, approximately 12 0.60%, approximately 12.70%, approximately 12.80%, approximately 12.90%, approximately 13.00%, approximately 13.10%, approximately 13.20%, approximately 13.30%, approximately 13.40%, approximately 13.50%, approximately 13.60%, approximately 13.70%, approximately 13.80%, approximately 13.90%, approximately 14.00%, approximately 14.10%, approximately 14.20%, approximately 14.30%, approximately 14.40%, approximately 14.50%, approximately 14.60%, approximately 14.70%, approximately 14.80%, approximately 14.90%, and approximately 15.00%.

[0052] In some embodiments, the composition comprises one or more of a binder, an emulsifier, and a disintegrant. In some embodiments, the composition further comprises between about 2.5% and about 7.5% by weight of polyvinylpyrrolidone. In some embodiments, the weight percentage of polyvinylpyrrolidone in the composition is selected from the group consisting of some embodiments, and the weight percentage of citric acid in the composition is selected from the group consisting of: about 2.50%, about 2.60%, about 2.70%, about 2.80%, about 2.90%, about 3.00%, about 3.10%, about 3.20%, about 3.30%, about 3.40%, about 3.50%, about 3.60%, about 3.70%, about 3.80%, about 3.90%, about 4.00%, about 4.10%, about 4.20%, about 4.30%, about 4.40%, about 4.50%, about 4 0.60%, approximately 4.70%, approximately 4.80%, approximately 4.90%, approximately 5.00%, approximately 5.10%, approximately 5.20%, approximately 5.30%, approximately 5.40%, approximately 5.50%, approximately 5.60%, approximately 5.70%, approximately 5.80%, approximately 5.90%, approximately 6.00%, approximately 6.10%, approximately 6.20%, approximately 6.30%, approximately 6.40%, approximately 6.50%, approximately 6.60%, approximately 6.70%, approximately 6.80%, approximately 6.90%, approximately 7.00%, approximately 7.10%, approximately 7.20%, approximately 7.30%, approximately 7.40%, and approximately 7.50%.

[0053] In some embodiments, the polyvinylpyrrolidone is crosslinked. In some embodiments, the weight percentage of crosslinked polyvinylpyrrolidone in the composition is selected from the group consisting of: about 2.50%, about 2.60%, about 2.70%, about 2.80%, about 2.90%, about 3.00%, about 3.10%, about 3.20%, about 3.30%, about 3.40%, about 3.50%, about 3.60%, about 3.70%, about 3.80%, about 3.90%, and about 4.00%.

[0054] In some embodiments, the composition further comprises a sugar alcohol. In some embodiments, the composition further comprises between about 5% and about 20.0% by weight of mannitol. In some embodiments, the weight percentage of mannitol in the composition is selected from the group consisting of: about 5.00%, about 5.10%, about 5.20%, about 5.30%, about 5.40%, about 5.50%, about 5.60%, about 5.70%, about 5.80%, about 5.90%, about 6.00%, about 6.10%, about 6.20%, about 6.30%, about 6.40%, about 6.50%, about 6.60%, about 6.70%, about 6.80%, about 6.90%, about 7.00%, about 7.10%, about 7.20%, about 7.30%, about 7.40%, about 7.50%, about 7.60%, about 7.70%, about 7.80%, about... 7.90%, approximately 8.00%, approximately 8.10%, approximately 8.20%, approximately 8.30%, approximately 8.40%, approximately 8.50%, approximately 8.60%, approximately 8.70%, approximately 8.80%, approximately 8.90%, approximately 9.00%, approximately 9.10%, approximately 9.20%, approximately 9.30%, approximately 9.40%, approximately 9.50%, approximately 9.60%, approximately 9.70%, approximately 9.80%, approximately 9.90%, approximately 10.00%, approximately 10.10%, approximately 10.20%, approximately 10.30%, approximately 10.40%, approximately 10.50%, approximately 10.60%, approximately 10.70%, approximately 10.80%, approximately 10.90%, approximately 11.00%. Approximately 11.10%, approximately 11.20%, approximately 11.30%, approximately 11.40%, approximately 11.50%, approximately 11.60%, approximately 11.70%, approximately 11.80%, approximately 11.90%, approximately 12.00%, approximately 12.10%, approximately 12.20%, approximately 12.30%, approximately 12.40%, approximately 12.50%, approximately 12.60%, approximately 12.70%, approximately 12.80%, approximately 12.90%, approximately 13.00%, approximately 13.10%, approximately 13.20%, approximately 13.30%, approximately 13.40%, approximately 13.50%, approximately 13.60%, approximately 13.70%, approximately 13.80%, approximately 13.90%, approximately 1 4.00%, approximately 14.10%, approximately 14.20%, approximately 14.30%, approximately 14.40%, approximately 14.50%, approximately 14.60%, approximately 14.70%, approximately 14.80%, approximately 14.90%, approximately 15.00%, approximately 15.10%, approximately 15.20%, approximately 15.30%, approximately 15.40%, approximately 15.50%, approximately 15.60%, approximately 15.70%, approximately 15.80%, approximately 15.90%, approximately 16.00%, approximately 16.10%, approximately 16.20%, approximately 16.30%, approximately 16.40%, approximately 16.50%, approximately 16.60%, approximately 16.70%, approximately 16.80%, approximately 16.90%, approximately 17.00%, approximately 17.10%, approximately 17.20%, approximately 17.30%, approximately 17.40%, approximately 17.50%, approximately 17.60%, approximately 17.70%, approximately 17.80%, approximately 17.90%, approximately 18.00%, approximately 18.10%, approximately 18.20%, approximately 18.30%, approximately 18.40%, approximately 1 8.50%, approximately 18.60%, approximately 18.70%, approximately 18.80%, approximately 18.90%, approximately 19.00%, approximately 19.10%, approximately 19.20%, approximately 19.30%, approximately 19.40%, approximately 19.50%, approximately 19.60%, approximately 19.70%, approximately 19.80%, approximately 19.90%, and approximately 20.00%.

[0055] In some embodiments, the composition further comprises a lubricant. In some embodiments, the composition further comprises between about 0.01% and about 2.0% by weight of magnesium stearate. In some embodiments, the magnesium stearate in the composition is expressed in weight percentages of about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.10%, about 0.11%, about 0.12%, about 0.13%, about 0.14%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.20%, about 0.21%, about 0.22%, about 0.23%, about 0.24%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0.30%, and about [other percentages]. 0.31%, approximately 0.32%, approximately 0.33%, approximately 0.34%, approximately 0.35%, approximately 0.36%, approximately 0.37%, approximately 0.38%, approximately 0.39%, approximately 0.40%, approximately 0.41%, approximately 0.42%, approximately 0.43%, approximately 0.44%, approximately 0.45%, approximately 0.46%, approximately 0.47%, approximately 0.48%, approximately 0.49%, approximately 0.50%, approximately 0.51%, approximately 0.52%, approximately 0.53%, approximately 0.54%, approximately 0.55%, approximately 0.56%, approximately 0.57%, approximately 0.58%, approximately 0.59%, approximately 0.60%, approximately 0.61%, approximately 0.62%, approximately 0.63%, approximately 0.6 4%, approximately 0.65%, approximately 0.66%, approximately 0.67%, approximately 0.68%, approximately 0.69%, approximately 0.70%, approximately 0.71%, approximately 0.72%, approximately 0.73%, approximately 0.74%, approximately 0.75%, approximately 0.76%, approximately 0.77%, approximately 0.78%, approximately 0.79%, approximately 0.80%, approximately 0.81%, approximately 0.82%, approximately 0.83%, approximately 0.84%, approximately 0.85%, approximately 0.86%, approximately 0.87%, approximately 0.88%, approximately 0.89%, approximately 0.90%, approximately 0.91%, approximately 0.92%, approximately 0.93%, approximately 0.94%, approximately 0.95%, approximately 0.96%, approximately 0.97%. Approximately 0.98%, approximately 0.99%, approximately 1.00%, approximately 1.01%, approximately 1.02%, approximately 1.03%, approximately 1.04%, approximately 1.05%, approximately 1.06%, approximately 1.07%, approximately 1.08%, approximately 1.09%, approximately 1.10%, approximately 1.11%, approximately 1.12%, approximately 1.13%, approximately 1.14%, approximately 1.15%, approximately 1.16%, approximately 1.17%, approximately 1.18%, approximately 1.19%, approximately 1.20%, approximately 1.21%, approximately 1.22%, approximately 1.23%, approximately 1.24%, approximately 1.25%, approximately 1.26%, approximately 1.27%, approximately 1.28%, approximately 1.29%, approximately 1.30%, approximately 1.31%, approximately 1.32%, approximately 1.33%, approximately 1.34%, approximately 1.35%, approximately 1.36%, approximately 1.37%, approximately 1.38%, approximately 1.39%, approximately 1.40%, approximately 1.41%, approximately 1.42%, approximately 1.43%, approximately 1.44%, approximately 1.45%, approximately 1.46%, approximately 1.47%, approximately 1.48%, approximately 1.49%, approximately 1.50%, approximately 1.51%, approximately 1.52%, approximately 1.53%, approximately 1.54%, approximately 1.55%, approximately 1.56%, approximately 1.57%, approximately 1.58%, approximately 1.59%, approximately 1.60%, approximately 1.61%, approximately 1.62%, approximately 1.63%, approximately 1.64%, approximately 1.65%, approximately 1.66%, approximately 1.67%, approximately 1.68%, approximately 1.69%, approximately 1.70%, approximately 1.71%, approximately 1.72%, approximately 1.73%, approximately 1.74%, approximately 1.75%, approximately 1.76%, approximately 1.77%, approximately 1.78%, approximately 1.79%, approximately 1.80%, approximately 1.81%, approximately 1.82%, approximately 1.83%, approximately 1.84%, approximately 1.85%, approximately 1.86%, approximately 1.87%, approximately 1.88%, approximately 1.89%, approximately 1.90%, approximately 1.91%, approximately 1.92%, approximately 1.93%, approximately 1.94%, approximately 1.95%, approximately 1.96%, approximately 1.97%, approximately 1.98%, approximately 1.99%, and approximately 2.00%. .

[0056] In one embodiment, this disclosure relates to dosage forms comprising aspirin, citric acid, sodium bicarbonate, and L-theanine. In some embodiments, the amount of aspirin in the dosage form is between about 300 mg and about 450 mg. In some implementations, the dosage form contains aspirin in the group consisting of the following: about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 376 mg, about 379 mg, about 380 mg, about 381 mg, about 395 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, and about 450 mg.

[0057] In some implementations, the amount of L-theanine in the dosage form is between about 300 mg and about 450 mg. In some embodiments, the amount of L-theanine in the dosage form is selected from the group consisting of: about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 376 mg, about 379 mg, about 380 mg, about 381 mg, about 395 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 378 mg, about 379 mg, and about 383 mg.

[0058] In some implementations, the amount of sodium bicarbonate in the dosage form is between about 200 mg and about 350 mg. In some embodiments, the amount of sodium bicarbonate in the dosage form is selected from the group consisting of: about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 261 mg, about 264 mg, about 266 mg, and about 269 mg.

[0059] In some embodiments, the amount of citric acid in the dosage form is between about 75 mg and about 200 mg. In some embodiments, the amount of citric acid in the dosage form is selected from the group consisting of: about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 131 mg, about 134 mg, about 136 mg, and about 137 mg.

[0060] In some embodiments, the dosage form comprises one or more of a binder, emulsifier, and disintegrant. In some embodiments, the dosage form further comprises a polyvinylpyrrolidone in an amount between about 50 mg and about 100 mg. In some embodiments, the amount of polyvinylpyrrolidone in the dosage form is selected from the group consisting of: about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 66 mg, about 69 mg, about 74 mg, and about 77 mg.

[0061] In some embodiments, the polyvinylpyrrolidone is cross-linked. In some embodiments, the amount of cross-linked polyvinylpyrrolidone in the dosage form is between about 25 mg and about 75 mg. In some embodiments, the amount of cross-linked polyvinylpyrrolidone in the dosage form is selected from the group consisting of: about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 43 mg, about 45 mg, about 50 mg, about 52 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, and about 75 mg.

[0062] In some embodiments, the dosage form further comprises a sugar alcohol. In some embodiments, the dosage form further comprises mannitol in an amount between about 50 mg and about 300 mg. In some embodiments, the amount of mannitol in the dosage form is selected from the group consisting of: 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 1... 80mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg, about 102mg, about 135mg, about 258mg, and about 269mg.

[0063] In some embodiments, the dosage form further comprises a lubricant. In some embodiments, the dosage form further comprises magnesium stearate in an amount between about 2.5 mg and about 15 mg. In some embodiments, the amount of magnesium stearate in the dosage form is selected from the group consisting of: about 2.50 mg, about 2.55 mg, about 2.60 mg, about 2.65 mg, about 2.70 mg, about 2.75 mg, about 2.80 mg, about 2.85 mg, about 2.90 mg, about 2.95 mg, about 3.00 mg, about 3.05 mg, about 3.10 mg, about 3.15 mg, about 3.20 mg, about 3.25 mg, about 3.30 mg, about 3.35 mg, about 3.40 mg, about 3.45 mg, about 3.50 mg, about 3.55 mg, about 3.60 mg, about 3.65 mg, about 3.70 mg, about 3.75 mg. Approximately 3.80 mg, approximately 3.85 mg, approximately 3.90 mg, approximately 3.95 mg, approximately 4.00 mg, approximately 4.05 mg, approximately 4.10 mg, approximately 4.15 mg, approximately 4.20 mg, approximately 4.25 mg, approximately 4.30 mg, approximately 4.35 mg, approximately 4.40 mg, approximately 4.45 mg, approximately 4.50 mg, approximately 4.55 mg, approximately 4.60 mg, approximately 4.65 mg, approximately 4.70 mg, approximately 4.75 mg, approximately 4.80 mg, approximately 4.85 mg, approximately 4.90 mg, approximately 4.95 mg, approximately 5.00 mg, approximately 5.05 mg, approximately 5.10 mg, approximately 5.15 mg, approximately 5.20 mg, approximately 5. 25mg, approximately 5.30mg, approximately 5.35mg, approximately 5.40mg, approximately 5.45mg, approximately 5.50mg, approximately 5.55mg, approximately 5.60mg, approximately 5.65mg, approximately 5.70mg, approximately 5.75mg, approximately 5.80mg, approximately 5.85mg, approximately 5.90mg, approximately 5.95mg, approximately 6.00mg, approximately 6.05mg, approximately 6.10mg, approximately 6.15mg, approximately 6.20mg, approximately 6.25mg, approximately 6.30mg, approximately 6.35mg, approximately 6.40mg, approximately 6.45mg, approximately 6.50mg, approximately 6.55mg, approximately 6.60mg, approximately 6.65mg, approximately 6.70mg g, approximately 6.75 mg, approximately 6.80 mg, approximately 6.85 mg, approximately 6.90 mg, approximately 6.95 mg, approximately 7.00 mg, approximately 7.05 mg, approximately 7.10 mg, approximately 7.15 mg, approximately 7.20 mg, approximately 7.25 mg, approximately 7.30 mg, approximately 7.35 mg, approximately 7.40 mg, approximately 7.45 mg, approximately 7.5 mg, approximately 7.60 mg, approximately 7.70 mg, approximately 7.80 mg, approximately 7.90 mg, approximately 8.00 mg, approximately 8.10 mg, approximately 8.20 mg, approximately 8.30 mg, approximately 8.40 mg, approximately 8.50 mg, approximately 8.60 mg, approximately 8.70 mg, approximately 8.80 mg, approximately 8.90mg, approximately 9.00mg, approximately 9.10mg, approximately 9.20mg, approximately 9.30mg, approximately 9.40mg, approximately 9.50mg, approximately 9.60mg, approximately 9.70mg, approximately 9.80mg, approximately 9.90mg, approximately 8.00mg, approximately 8.10mg, approximately 8.20mg, approximately 8.30mg, approximately 8.40mg, approximately 8.50mg, approximately 8.60mg, approximately 8.70mg, approximately 8.80mg, approximately 8.90mg, approximately 9.00mg, approximately 9.25mg, approximately 9.50mg, approximately 9.7 5 mg, approximately 10.00 mg, approximately 10.25 mg, approximately 10.50 mg, approximately 10.75 mg, approximately 11.00 mg, approximately 11.25 mg, approximately 11.50 mg, approximately 11.75 mg, approximately 12.00 mg, approximately 12.25 mg, approximately 12.50 mg, approximately 12.75 mg, approximately 13.00 mg, approximately 13.25 mg, approximately 13.50 mg, approximately 13.75 mg, approximately 14.00 mg, approximately 14.25 mg, approximately 14.50 mg, approximately 14.75 mg, and approximately 15.00 mg.

[0064] Derivatives prepared using the aspirin, citric acid, sodium bicarbonate, and L-theanine cocrystal composition according to embodiments of the present invention can be administered sublingually.

[0065] The pharmaceutical composition according to embodiments of the present invention can be prepared as orally disintegrating tablets, oral liquids, instant solvents, granules, rice paper capsules (films), pills, or powders.

[0066] Embodiments of the present invention include water-soluble excipients with optimal disintegration properties.

[0067] The eutectic according to embodiments of the present invention can be used to improve one or more physical properties of a selected therapeutic or preventative active pharmaceutical ingredient, such as solubility, stability, and dissolution rate.

[0068] The invention is described in further detail by way of examples, but it is not intended to limit the scope of the invention to these examples only. Although specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the invention, it should be understood that the invention may be embodied in other ways without departing from such principles.

[0069] Theanine cocrystals, including aspirin / theanine cocrystals, are described in U.S. Patent Nos. 9,603,937, 9,603,938, 9,603,939, 9,289,438, 9,289,439, 9,289,440, 8,685,948, 8,476,250, 8,304,404, and 8,173,625, which are incorporated herein by reference in their entirety.

[0070] References 1. “Heart Disease and Stroke Statistics 2017 At-a-Glance.” https: / / www.heart.org / idc / groups / ahamah-public / @wcm / @sop / @smd / ...N.p., n.d. Web. 2. Virmani, Renu. “Pathophysiology of Acute Myocardial Infarction.” Medical Clinics of North America, by Allen P. Burke, Blackwell, 2007, pp. 88 - 89. 3. Liu, Jiaqi, et al. “Inflammation and Inflammatory Cells in Myocardial Infarction and Reperfsion Injury: A Double-Edged Sword,” Clinical Medicine Insights: Cardiology, vol. 10, 2016, doi: 10.4137 / cmc.s33164. 4. PDR for Nutritional Supplements 2nd.ed. Thomson Reuters, Montvale, NJ 2008, p. 366. 5. “FDA; GRAS Assessment of L-Theanine(98%).” http: / / www.accessdata.fda.gov / scripts / fcn / gras_notices / GRN000338.pdf. N.p., 5 May 2010. 6.Gomez-Ramirez,Manuel,et al.“The Deployment of IntersensorySelective Attention:A High-density Electrical Mapping Study of the Effects ofTheanine”:Clinical Neuropharmacology.”LWW.Clinical Neuropharmacology:January / February2007-Volume30-Issue l-pp.25-38,n.d.Web.21Apr.2017. 7.“L-Theanine”http: / / www.chemicalbook.com / ChemicalProduct Property_EN_CB1485976.htm. 8.Jaiswal,Manoj,et al.“Impairment of Mitochondrial Calcium Handlingin a mtSODI Cell Culture Model of Motoneuron Disease.”BMC Neuroscience,vol.10,no.1,2009,p.64.,doi:10.1186 / 1471-2202-10-64. 9.Manev,H.:Favaron,M.;Guidotti,A.;and Costa,E.,Delayed increase ofCa 2+ influx elicited by glutamate:role in neuronal death.MolecularPharmacology.1989Jul.;36(1):106-112). 10.Yokogoshi,Hidehiko;Kobayashi,Miki;Mochizuki,Mikiko;and Terashima,Takehiko,“Effect of Theanine,Glutamylethylamide,on Brain Monoamines andStriatal Dopamine Release in Conscious Rats.”Neurochemical Research,May1998,Volume23,Issue 5,pp.667-673). 11.Alternative Medicine Review,Vol.10,Number2,p.136,2005,ThorneResearch Inc. 12.Sadzuka,Yasuyuki,et al.“Enhancement of the Activity of Doxorubicinby Inhibition of Glutamate Transporter.”Toxicology Letters,vol.123,no.-2-3,2001,pp.159-167.,doi;10:10116 / s0378-4274(01)00391-5. 13.Peat,Ray.“Aspirin,Brain,and Cancer.”Serotonin:Effects inDisease.Aging and inflammation,raypeat.com / articles / aging / aspirin-brain-cancer.shtml. 14.BTIscience.“Aspirin Targets Key Protein in NeurodegenerativeDisease.”EurekAlertl,30Nov.2015,www.eurekalert.org / pub_realeases / 2015-11 / btif-atk112515.php. 15. Choi, Hyong Woo, et al. "Human GAPDH Is a Target of Aspirinas Primary Metabolite Salicylic Acid and Its Derivatives." Plos One, vol.10, no.11, 2015, doi: 10, 1371 / iournal.pone.0143447. Each of the references cited above is incorporated in its entirety into this article as if it were fully described herein. This disclosure also includes the following implementation schemes: 1. A composition comprising aspirin, citric acid, sodium bicarbonate and L-theanine. 2. A method for preparing a composition comprising aspirin, citric acid, sodium bicarbonate and L-theanine. 3. A cocrystallized sublingual formulation of aspirin, citric acid, sodium bicarbonate, and L-theanine, wherein, compared to the conventional oral route of aspirin, the formulation can bypass the first-pass effect of the liver when rapid onset of action is required, and has improved dissolution rate and bioavailability. 4. A cocrystallized sublingual formulation of aspirin, citric acid, sodium bicarbonate, and L-theanine, which, compared with conventional oral aspirin, has the expected significantly reduced median platelet aggregation inhibition time. 5. A water-soluble cocrystal product of acetylsalicylic acid, citric acid, sodium bicarbonate, and L-theanine, administered sublingually for the treatment of acute myocardial infarction. 6. Cocrystal compositions of drugs from a specific class of pharmaceuticals with enantiomers, L- and D-isomers, D,L-racemic mixtures, S- and R-isomers, S,R-racemic mixtures, all rotational isomers, tautomers, salt forms, and hydrates of theanine, wherein the N-substituted functional R1-group [C4 or γ-CH2-C(O)--NR1] may contain straight-chain, cyclic, or branched alkyl groups and their derivatives; straight-chain, cyclic, or branched alkenyl groups and their derivatives; and aromatic groups (which may be aryl groups) and their derivatives, constituting all analogous forms of theanine. 7. The composition according to embodiment 1, wherein aspirin, citric acid, sodium bicarbonate and L-theanine are in eutectic form. 8. A dosage form comprising a composition containing aspirin, citric acid, sodium bicarbonate and L-theanine. 9. The dosage form described in Implementation Scheme 8, wherein the dosage form is an orally disintegrating tablet or a certain amount of powder. 10. A method of treating an acute myocardial infarction in a subject in need of treatment, comprising administering to the subject a cocrystallized aspirin, citric acid, sodium bicarbonate, and a sublingual formulation of L-theanine. 11. The method of implementation scheme 10, wherein the aspirin, citric acid, sodium bicarbonate, and L-theanine cocrystal are absorbed in the bloodstream of the subject via the sublingual route, bypassing the first-pass effect of the liver. 12. The composition of embodiment 1, wherein the weight percentage of aspirin in the composition is between about 20% and about 30%. 13. The composition of embodiment 1, wherein the weight percentage of aspirin in the composition is selected from the group consisting of about 24.4%, about 25.0%, about 27.4%, and about 27.5%. 14. The composition of embodiment 1, wherein the weight percentage of L-theanine in the composition is between about 20% and about 30%. 15. The composition of embodiment 1, wherein the weight percentage of L-theanine in the composition is selected from the group consisting of about 24.6%, about 25.2%, about 27.7%, and about 27.8%. 16. The composition of embodiment 1, wherein the weight percentage of sodium bicarbonate in the composition is between about 15% and about 25%. 17. The composition of embodiment 1, wherein the weight percentage of sodium bicarbonate in the composition is selected from the group consisting of about 16.9%, about 17.4%, about 19.4%, and about 19.5%. 18. The composition of embodiment 1, wherein the citric acid content in the composition is between about 5% and about 15% by weight. 19. The composition of embodiment 1, wherein the citric acid in the composition is selected from the group consisting of about 8.8%, about 9.1%, about 9.6%, and about 9.7% by weight. 20. The composition of embodiment 1, further comprising one or more of an adhesive, an emulsifier, and a disintegrant. 21. The composition of embodiment 1, further comprising between about 2.5% and about 7.5% by weight of polyvinylpyrrolidone. 22. The composition of embodiment 21, wherein the weight percentage of polyvinylpyrrolidone in the composition is selected from the group consisting of about 4.8%, about 4.9%, and about 5.0%. 23. The composition of any one of embodiments 21 or 22, wherein the polyvinylpyrrolidone is crosslinked. 24. The composition of embodiment 23, wherein the weight percentage of crosslinked polyvinylpyrrolidone in the composition is selected from the group consisting of about 3.1% and about 3.3%. 25. The composition of embodiment 1, further comprising sugar alcohol. 26. The composition of embodiment 1, further comprising between about 5% and about 20.0% by weight of mannitol. 27. The composition of embodiment 26, wherein the mannitol in the composition is selected from the group consisting of about 7.4%, about 9.8%, about 16.5%, and about 17.9% by weight. 28. The composition of embodiment 1, further comprising a lubricant. 29. The composition of embodiment 1, further comprising between about 0.01% and about 2.0% by weight of magnesium stearate. 30. The composition of embodiment 29, wherein the magnesium stearate in the composition is about 0.5% by weight. 31. The dosage form described in embodiment 8, wherein the amount of aspirin in the dosage form is between about 300 mg and about 450 mg. 32. The dosage form of embodiment 8, wherein the amount of aspirin in the dosage form is selected from the group consisting of about 376 mg, about 379 mg and about 381 mg. 33. The dosage form described in embodiment 8, wherein the amount of L-theanine in the dosage form is between about 300 mg and about 450 mg. 34. The dosage form of embodiment 8, wherein the amount of L-theanine in the dosage form is selected from the group consisting of: about 378 mg, about 379 mg and about 383 mg. 35. The dosage form described in Embodiment 8, wherein the amount of sodium bicarbonate in the dosage form is between about 200 mg and about 350 mg. 36. The dosage form of embodiment 8, wherein the amount of sodium bicarbonate in the dosage form is selected from the group consisting of: about 261 mg, about 264 mg, about 266 mg and about 269 mg. 37. The dosage form described in embodiment 8, wherein the amount of citric acid in the dosage form is between about 75 mg and about 200 mg. 38. The dosage form of embodiment 8, wherein the amount of citric acid in the dosage form is selected from the group consisting of: about 131 mg, about 134 mg, about 136 mg and about 137 mg. 39. The dosage form described in Embodiment 8, further comprising one or more of a binder, an emulsifier, and a disintegrant. 40. The dosage form described in Embodiment 8 further comprises an amount of polyvinylpyrrolidone between about 50 mg and about 100 mg. 41. The dosage form of embodiment 40, wherein the amount of polyvinylpyrrolidone in the dosage form is selected from the group consisting of: about 66 mg, about 69 mg, about 74 mg and about 77 mg (4.9%). 42. The dosage form of any one of embodiments 40 or 41, wherein the polyvinylpyrrolidone is crosslinked. 43. The dosage form of embodiment 42, wherein the amount of crosslinked polyvinylpyrrolidone in the dosage form is between about 25 mg and about 75 mg. 44. The dosage form according to any one of embodiments 42 or 43, wherein the amount of crosslinked polyvinylpyrrolidone in the dosage form is selected from the group consisting of about 43 mg and about 52 mg. 45. The dosage form described in Implementation Scheme 8, further comprising sugar alcohols. 46. ​​The dosage form described in Embodiment 8, further comprising an amount of mannitol between about 50 mg and about 300 mg. 47. The dosage form of embodiment 46, wherein the amount of mannitol in the dosage form is selected from the group consisting of: about 102 mg, about 135 mg, about 258 mg and about 269 mg. 48. The dosage form described in embodiment 8, further comprising a lubricant. 49. The dosage form described in Embodiment 8, further comprising an amount of magnesium stearate between about 2.5 mg and about 15 mg. 50. The dosage form of embodiment 49, wherein the amount of magnesium stearate in the dosage form is selected from the group consisting of: about 7.0 mg, about 7.5 mg and about 8 mg.

Claims

1. A composition comprising aspirin, citric acid, sodium bicarbonate and L-theanine.

2. A method for preparing a composition comprising aspirin, citric acid, sodium bicarbonate and L-theanine.

3. A cocrystallized sublingual formulation of aspirin, citric acid, sodium bicarbonate, and L-theanine, wherein, compared to the conventional oral route of aspirin, the formulation can bypass the first-pass effect of the liver when rapid onset of action is required, and has improved dissolution rate and bioavailability.

4. A cocrystallized sublingual formulation of aspirin, citric acid, sodium bicarbonate, and L-theanine, which, compared with conventional oral aspirin, has the expected significantly reduced median platelet aggregation inhibition time.

5. A water-soluble cocrystal product of acetylsalicylic acid, citric acid, sodium bicarbonate, and L-theanine, administered sublingually for the treatment of acute myocardial infarction.

6. Cocrystal compositions of drugs from a particular class with enantiomers, L- and D-isomers, D,L-racemic mixtures, S- and R-isomers, S,R-racemic mixtures, all rotational isomers, tautomers, salt forms, and hydrates of theanine, wherein the N-substituted functional R1-group [C4 or γ-CH2-C(O)—NR1] may contain straight-chain, cyclic, or branched alkyl groups and their derivatives; straight-chain, cyclic, or branched alkenyl groups and their derivatives; and aromatic groups (which may be aryl groups) and their derivatives, constituting all analog forms of theanine.

7. The composition of claim 1, wherein aspirin, citric acid, sodium bicarbonate and L-theanine are in eutectic form.

8. A dosage form comprising a composition containing aspirin, citric acid, sodium bicarbonate and L-theanine.

9. The dosage form of claim 8, wherein the dosage form is an orally disintegrating tablet or a certain amount of powder.

10. Use of cocrystallized aspirin, citric acid, sodium bicarbonate, and L-theanine in the preparation of a sublingual formulation for the treatment of acute myocardial infarction in subjects in need of treatment.

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