HK40029182A - Sublingual formulation with water-soluble cocrystals of acetylsalicylic acid with citric acid, sodium bicarbonate, and l-theanine for the treatment of acute myocardial infarction - Google Patents

Description

Sublingual formulation with water soluble cocrystals of acetylsalicylic acid with citric acid, sodium bicarbonate and L-theanine for the treatment of acute myocardial infarction

Technical Field

The present invention relates to a novel sublingual formulation for the treatment of acute myocardial infarction using a water-soluble eutectic product of acetylsalicylic acid with citric acid, sodium bicarbonate and L-theanine.

Background

Heart disease remains a leading cause of death in the united states. In the united states, about 790,000 people have heart attacks each year. Of these, about 114,000 will die. In the united states, the estimated annual incidence of heart attacks is 580,000 new attacks and 210,000 recurrent attacks. The average age of men at the first heart attack is 65.3 years and women are 71.8 years. About every 40 seconds, one american will have a heart attack. Most out-of-home cardiac arrest (OHCA) occurs in the home or residence (70%), with public spaces (19.8%) and nursing homes (10.6%) being the second and third most common locations for OHCA. Heart attack ($115 million) and coronary heart disease ($104 million) are 2 of the 10 most expensive major hospital discharge diagnoses.

Disclosure of Invention

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 of making a composition comprising aspirin with citric acid, sodium bicarbonate, and L-theanine. In some embodiments, the present invention relates to a co-crystal aspirin, citric acid, sodium bicarbonate, L-theanine sublingual formulation, wherein the formulation can bypass the hepatic first pass effect when a rapid onset of action is desired, with improved dissolution rate and bioavailability compared to the oral route of conventional aspirin. In one embodiment, the present invention relates to a eutectic aspirin, citric acid, sodium bicarbonate, L-theanine sublingual formulation that is expected to significantly reduce the median platelet aggregation inhibition time compared to the oral route of conventional aspirin. In one embodiment, the invention relates to the sublingual administration of a water-soluble co-crystal product of acetylsalicylic acid with citric acid, sodium bicarbonate and L-theanine for the treatment of acute myocardial infarction.

In some embodiments, the invention relates to co-crystal compositions of the drug with the α and β amino acid enantiomers, L-and D-isomers, D, L-racemic mixture, S-and R-isomers, S, R-racemic mixture, all rotamers, tautomers, salt forms and hydrates of theanine, wherein the N-substituted functional R is₁A group [ C ]₄Or gamma-CH₂-C(O)—NR1]May contain straight, cyclic or branched alkyl groups and derivatives thereof; linear, cyclic or branched alkenyl groups and derivatives thereof; and aromatic groups (which may be aryl groups) and derivatives thereof, which constitute all analogue forms of theanine.

In some embodiments, the present invention relates to one or more of the following pharmaceutical formulations:

formulation # 4

The disintegration time was less than 1 minute for all formulations.

In one embodiment, the present disclosure relates to a composition comprising aspirin, citric acid, sodium bicarbonate, and L-theanine. In some embodiments, the weight% of aspirin in the composition is between about 20% and about 30%. In some embodiments, the weight% 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% of L-theanine in the composition is between about 20% and about 30%. In some embodiments, the weight% 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% of sodium bicarbonate in the composition is between about 15% and about 25%. In some embodiments, the weight% 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% of citric acid in the composition is between about 5% and about 15%. In some embodiments, the weight% 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, an emulsifier, and a disintegrant. In some embodiments, the composition further comprises between about 2.5% and about 7.5% by weight polyvinylpyrrolidone. In some embodiments, the weight% 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% 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 mannitol. In some embodiments, the weight% of mannitol in the composition is selected from the group consisting of: about 7.4%, about 9.8%, about 16.5% and about 17.9%. 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 magnesium stearate. In some embodiments, the weight% of magnesium stearate in the composition is about 0.5%.

In one embodiment, the present 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 376mg, 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 378mg, 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 261mg, about 264 mg, about 266 mg and about 269 mg. In some embodiments, the amount of citric acid in the dosage form is between about 75mg and about 200 mg. In some embodiments, the amount of citric acid in the dosage form is selected from the group consisting of: about 131mg, about 134 mg, about 136 mg and about 137 mg. In some embodiments, the dosage form comprises one or more of a binder, an emulsifier, and a disintegrant. In some embodiments, the dosage form further comprises polyvinylpyrrolidone in an amount between about 50mg and about 100 mg. In some embodiments, 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. In some embodiments, the polyvinylpyrrolidone is crosslinked. In some embodiments, the amount of cross-linked polyvinylpyrrolidone in the dosage form is between about 25mg 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 43mg and about 52 mg. 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 50mg and about 300 mg. In some embodiments, the amount of mannitol in the dosage form is selected from the group consisting of: about 102mg, about 135mg, 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.

In some embodiments, the present invention relates to a method of treating acute myocardial infarction in a subject in need thereof, the method comprising administering to the subject sublingual aspirin in a co-crystal with citric acid, sodium bicarbonate, and L-theanine. In one embodiment, sublingual aspirin, citric acid, sodium bicarbonate, L-theanine co-crystal are directly absorbed in the subject's bloodstream, and bypass the hepatic first pass effect.

Detailed Description

Early administration of a new sublingual aspirin, citric acid, sodium bicarbonate, L-theanine co-crystal formulation for the treatment of acute myocardial infarction is of paramount importance and may begin to benefit the patient within minutes, whereas the full benefit of traditional aspirin may not be effective until major sequelae (such as ventricular tachycardia, ventricular fibrillation, complete cardiac conduction block, or death) have occurred. Thus, there is a clear unmet need for a novel sublingual aspirin, citric acid, sodium bicarbonate, L-theanine co-crystal formulation with improved pharmacokinetics and pharmacodynamics in patients with acute myocardial infarction. The present invention satisfies these and other medical needs and overcomes the deficiencies of the prior art.

Advantages of the eutectic sublingual formulation of aspirin, citric acid, sodium bicarbonate, L-theanine include improved dissolution rate and bioavailability when a rapid onset of action is desired, as compared to the oral route of conventional aspirin. The vascular network of the sublingual vessels provides increased drug absorption compared to the oral route. Thus, the sublingual network of blood vessels results in a faster dissolution rate, especially if the pH of saliva is greater than 6. The sublingual route bypasses the hepatic first pass effect, resulting in increased bioavailability of the drug, as the drug is absorbed directly into the systemic circulation rather than through the gastrointestinal tract, where the drug is first delivered to the liver through the portal vein and then metabolized in the liver prior to entering the systemic circulation. Patients with a history of acute coronary syndrome may self-administer the co-crystal aspirin, citric acid, sodium bicarbonate, L-theanine sublingual formulation at home or at work, prior to the arrival of an ambulance, in the field, or during the onset of acute chest pain during air travel. Patients with a history of dysphagia (dysphagia) or a history of swallowing pain (pain when swallowing) will benefit from the sublingual route.

One significant drawback of the sublingual route occurs in patients who smoke. Smokers will not fully benefit from the sublingual route because smoking causes vasoconstriction of blood vessels, which reduces absorption of the drug.

The continuing interest in improving pharmaceutical substances with less than ideal physical properties has led to significant research into problems associated with polymorphism and solvatomorphism (solvatomorphism). Recently, it has been recognized that many substances can be co-crystallized in a single continuous lattice structure, thereby introducing pharmaceutical scientists into a new field of crystal engineering.

Co-crystals are mixed crystals, where co-crystals are structurally homogeneous crystalline materials that have been formed from discrete neutral molecular species that are solid at ambient temperature. A co-crystal is characterized by two or more molecules that are associated at the molecular level but not bonded.

The co-crystals represent a novel form of the drug substance which would be suitable for incorporation into a pharmaceutical solid dosage form and should enable the formulation scientist to overcome various problems encountered during the development of conventional formulations. One can consider the co-crystals as a replacement for polymorphs, solvated forms (solvatomorph) and salts, as co-crystals represent a different approach to solving problems related to e.g. dissolution, crystallinity and hygroscopicity.

Co-crystals are attractive to the pharmaceutical industry because they provide an opportunity to alter the chemical and/or physical properties of an API without the need to form or break covalent bonds.

Unfortunately, it has not been possible to predict whether two substances will co-crystallize, and therefore eutectic screening studies are largely empirical in nature.

Given the structural similarity of glutamine and glutamic acid to theanine, and the fact that neither glutamine nor glutamic acid forms a co-crystal with aspirin, one may have been led to the inference that theanine will also not form a co-crystal with aspirin. Despite this expectation, aspirin does form a co-crystal with theanine, but aspirin does not form a co-crystal with glutamine or glutamic acid.

The conformational isomers described below are highly structurally related to L-theanine:

(L) -theanine	(L) -Glutamine	(L) -glutamic acid

Co-crystal engineering can be used to improve one or more physical properties, such as solubility, stability and dissolution rate, of a selected therapeutically or prophylactically active pharmaceutical ingredient.

Salicylic acid is an active metabolite of aspirin.

Therapeutic compounds, such as aspirin, are the most stable in crystalline form, but may exhibit poor water solubility and slow dissolution rates. These properties have a tendency to reduce the bioavailability of the Active Pharmaceutical Ingredient (API), thereby slowing absorption.

Myocardial infarction is most often caused by the rupture of atherosclerotic lesions in the coronary arteries. This rupture causes the formation of a coronary thrombus or clot which occludes the artery preventing it from supplying blood and oxygen to the myocardium normally supplied by that vessel. As a result, ischemic death of the cardiomyocytes ensues.

Activated macrophages and T lymphocytes at the site of plaque rupture release metalloproteinases and cytokines that weaken the fibrotic cap making it susceptible to erosion or tearing due to the shear stress exerted by blood flow. Plaque rupture exposes subendothelial collagen, which serves as a site for platelet adhesion, activation, and aggregation. This results in a substance (e.g. thromboxane A)₂Fibrinogen, fibrinogen5-hydroxytryptamine (serotonin), platelet activating factor and ADP (adenosine diphosphate)) which further promotes platelet aggregation. Activation of the coagulation cascade leads to fibrin formation and the spread of an obstructive thrombus. When a thrombus forms on the ruptured plaque, it eventually occludes the artery. Atherosclerotic plaque rupture with superimposed thrombosis accounted for 95% of cases of acute myocardial infarction.

Inflammation and inflammatory cell infiltration are markers of myocardial infarction and reperfusion injury. Ischemic heart injury activates the innate immune response through Toll-like receptors and upregulates chemokine and cytokine expression 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 regression of inflammation, infarction healing, angiogenesis and ventricular remodeling. The deleterious and beneficial effects in the pathophysiology of Myocardial Infarction (MI) and reperfusion injury may be due to the subpopulation heterogeneity and functional diversity of these inflammatory cells.

Aspirin irreversibly inhibits platelet cyclooxygenase 1(COX-1) by acetylation of the amino acid serine at position 529, thereby preventing arachidonic acid from entering the COX-1 catalytic site by steric hindrance. By inhibiting COX-1, platelets cannot synthesize prostaglandin H2, which would otherwise be converted to thromboxane a2, thromboxane a2 causing platelet aggregation, an early step in the coagulation cascade.

Theanine is present in green tea plant (tea tree)Camellia sinensis) And inedible mushroom Boletus luteus (A. luteus (Fr.) pers.)Xerocomus badius) But are otherwise rare in nature. Tea is the second most widely consumed beverage in the world. Monks have been drinking tea containing theanine for over 4,000 years. L-theanine is a component of fruit juices and beverages, non-herbal teas, sports drinks, bottled water, chocolate bars, hard candies, mints, and chewing gums. Theanine is extremely safe, with LD50 toxicity > 5000 mg/kg in rats. According to the FDA GRAS evaluation of L-theanine (based on statistical analysis of potential dietary intake), an average theanine consumption of 682 mg/person/day and a 90 th percentile consumption of 1284 mg (1.28g) — based on a statistical analysis of potential dietary intake were estimatedPerson/day.

L-theanine (N-ethyl-L-glutamine) is an amino acid analog of glutamine, 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) accession number 3081-61-6 and GRAS classification (GRAS Notification number: GRN 000209). L-theanine has empirical formula C₇H₁₄N₂O₃Molecular weight 174.20, pKa 2.35, and melting point 217-218 ℃. In the kidney, glutaminase hydrolyses theanine to glutamate and ethylamine.

Chemical structure of L-theanine

Theanine is itself a potent inhibitor of thrombin-stimulated thromboxane preparations in whole blood, thus, theanine has an anticoagulant effect when co-crystals of aspirin with citric acid, sodium bicarbonate and L-theanine are administered sublingually, such anticoagulant effect of theanine may be beneficial in the treatment of acute myocardial infarction.

Theanine enhances the solubility of aspirin in water. As 5-N-ethylglutamine, theanine differs from glutamine in that CH₂-CH₃The ionic charge is available for pairing with the ortho carboxylate anion of acetylsalicylic acid through the cationic or protonated α amino group, which can be further stabilized by hydrogen bonding to the nitrogen of the ethylcarboxamide (the acetamido group is a functional marker for theanine-type molecules)Either molecule alone encapsulates more water molecules. This allows the complex to be easily solvated when it is dissolved in water or a buffer.

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

Excitotoxicity is a pathological process responsible for neuronal cell death due to excessive stimulation of neurotransmitters (e.g. glutamate). Pathologically high levels of glutamate can be detected by allowing high levels of calcium ion (Ca)²⁺) Enter cells and cause excitotoxicity. This calcium (Ca)²⁺) Theanine has been shown to bind to AMPA (α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate, NMDA (N-methyl-D-aspartate), and group 1 mGluR receptors, thus antagonizing excitatory neurotransmitters.

GABA (gamma-aminobutyric acid) is the most widespread inhibitory neurotransmitter of the brain. When GABA levels are reduced, nerve impulses in neurons increase. Theanine increases GABA levels in the brain and counters the over-stimulation of nerve impulses by excitatory neurotransmitters (e.g., glutamate), which can be found in patients with stroke and traumatic brain injury.

L-theanine crosses the blood brain barrier through a large, neutral amino acid leucine-preferred transport system, 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 the concentration of serotonin and dopamine in the brain would be beneficial in treating migraine sufferers where serotonin and dopamine levels are generally reduced.

The novel sublingual water-soluble co-crystals of aspirin with citric acid, sodium bicarbonate and L-theanine crossing the blood brain barrier will have a neuroprotective effect on a number 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.

Researchers at Boyce Thompson Institute and John Hopkins University found that salicylic acid, the active metabolite of aspirin, binds to glyceraldehyde 3-phosphate dehydrogenase (GAPDH), preventing the enzyme from entering the nucleus of neurons where it enhances protein turnover, leading to cell death. GAPDH is thought to play an important role in neurodegenerative diseases, including alzheimer's disease, parkinson's disease, and huntington's disease. The new sublingual water-soluble co-crystal of aspirin with citric acid, sodium bicarbonate and L-theanine crossing the blood brain barrier would be of paramount importance in preventing neuronal cell death by binding salicylic acid to glyceraldehyde 3-phosphate dehydrogenase.

Theanine inhibits the efflux of chemotherapeutic agents (e.g., doxorubicin, idarubicin, cisplatin, and irinotecan), resulting in elevated drug levels in cancer cells, which strongly inhibits the tumor. Theanine blocks the export of doxorubicin, idarubicin, cisplatin and irinotecan from cancer cells by blocking glutamate and glutathione transport mechanisms. Cancer cells detoxify doxorubicin, idarubicin, cisplatin, and irinotecan using glutathione and deliver the drug out of the cells. Theanine can interfere with this process due to its structural similarity to glutamate.

The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operation, advantages, and specific objects attained by its uses, reference is made to the accompanying descriptive matter in which preferred embodiments of the invention are illustrated.

It is therefore an object of the present invention to provide a method of using a co-crystal composition of aspirin with citric acid, sodium bicarbonate and L-theanine, which is easily administered to a human by the sublingual route, bypassing the hepatic first pass effect, increasing the dissolution rate and bioavailability.

It is another object of the present invention to provide a water-soluble aspirin, citric acid, sodium bicarbonate, theanine co-crystal composition having the above characteristics and which is rapidly soluble in water.

It is another object of the present invention to provide a water-soluble aspirin, citric acid, sodium bicarbonate, theanine co-crystal formulation suitable for sublingual administration which has the above characteristics and which allows rapid delivery of acetylsalicylic acid into the bloodstream.

It is yet another object of the present invention to provide a water-soluble aspirin, citric acid, sodium bicarbonate, theanine co-crystal formulation suitable for sublingual administration which has the above characteristics and which allows rapid delivery of therapeutic amounts of theanine into the bloodstream.

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

It is a still further object of the present invention to provide a water-soluble aspirin, citric acid, sodium bicarbonate, theanine co-crystal composition suitable for sublingual administration having the above characteristics and which is expected to reduce the median platelet aggregation inhibition time compared to the oral route of conventional aspirin.

It is a still further object of the present invention to provide a water-soluble eutectic formulation of aspirin, citric acid, sodium bicarbonate, theanine, suitable for sublingual administration, which has the above characteristics and which bypasses the gastrointestinal tract without causing irritation, erosion or bleeding of the gastrointestinal tract that may occur with conventional oral aspirin use.

Embodiments of the invention may include eutectic compositions of the α and β amino acid enantiomers, L-and D-isomers, D, L-racemic mixtures, S-and R-isomers, S, R-racemic mixtures, all rotamers, tautomers, salt forms and hydrates, of a drug and theanine from the classes listed below, wherein the N-substituted functional R₁A group [ C ]₄Or gamma-CH₂-C(O)—NR1]May contain straight, cyclic or branched alkyl groups and derivatives thereof; linear, cyclic or branched alkenyl groups and derivatives thereof; and aromatic groups (which may be aryl groups) and derivatives thereof, which constitute all analogue forms of theanine.

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.

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

Sodium bicarbonate is a white crystalline powder that is very soluble in water and has the molecular formula NaHCO₃CAS number 144-55-8, molecular weight 84.006g/mol, pKa 6.4 and 10.3. Without being bound by a particular theory of the invention, sodium bicarbonate (NaHCO)₃) Deprotonating the carboxylic acid of aspirin to produce the sodium acetylsalicylate salt, which is more soluble in water due to the presence of the charged carboxylate group. Aspirin hydrolysis is pH independent between pH 5 and 8, which means that up to the saturation range, bicarbonate is the specific base catalyst for the production of aspirin anion. Hydrolysis of acetate by aspirin is independent of pH and depends only on the concentration of aspirin carboxylate anion. At molar equivalents greater than 1.2, the abstraction of protons from the acid of aspirin is ultra-fast and complete.

Citric acid, 2-hydroxypropane-1, 2, 3-tricarboxylic acid, CAS number 77-92-9, molecular formula C₆H₈O₇Having a molecular weight of 192.12 g/mol. Is easily dissolved in water. It is a tribasic having pKa 1-3 of 5.21, 4.28 and 2.92. Under physiological conditions, one of the acid groups is deprotonated, which allows the conjugate base of the acid to bind to other molecules. The acidic citric acid solubilizes calcium ion-based coagulants by sequestering calcium out of the clot complex in the blood. Thus, citrate has an anticoagulant effect due to its ability to chelate calcium. This anticoagulant effect would be beneficial to patients suffering from acute myocardial infarction when administered sublingual aspirin, citric acid, sodium bicarbonate, L-theanine cocrystal. Citric acid in the formulation reacts with sodium bicarbonate, resulting in a buffer, disintegrant and favorable compressibility.

In one embodiment, the present disclosure relates to a composition comprising aspirin, citric acid, sodium bicarbonate, and L-theanine. In some embodiments, the weight% of aspirin in the composition is between about 20% and about 30%. In some embodiments, the weight% 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 22.20%, about 22.30%, about 22.40%, about 22.50%, about 2%, about 22.70%, about 22.80%, about 22.90%, about 23.00%, about 23.10%, about 23.20%, about 23.30%, about 23.40%, about 23.50%, about 23.60%, about 23.70%, about 23.80%, about 23.90%, about 24.00%, about 24.10%, about 24.20%, about 24.30%, about 24.40%, about 24.50%, about 25.25%, about 20.30%, about 25.30%, about 25.25%, about 25.30%, about 25.25%, about 26%, about 25.30%, about 25.25%, about 25.30%, about 25%, about 25.25%, about 25%, about 25.30%, about 25%, about 25.30, About 26.50%, about 26.60%, about 26.70%, about 26.80%, about 26.90%, about 27.00%, about 27.10%, about 27.20%, about 27.30%, about 27.40%, about 27.50%, about 27.60%, about 27.70%, about 27.80%, about 27.90%, about 28.00%, about 28.10%, about 28.20%, about 28.30%, about 28.40%, about 28.50%, about 28.60%, about 28.70%, about 28.80%, about 28.90%, about 29.00%, about 29.10%, about 29.20%, about 29.30%, about 29.40%, about 29.50%, about 29.60%, about 29.70%, about 29.80%, about 29.90%, and about 30.00%.

In some embodiments, the weight% of L-theanine in the composition is between about 20% and about 30%. In some embodiments, the weight% 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%, about 22.30%, about 22.40%, about 22.50%, about 2%, about 22.70%, about 22.80%, about 22.90%, about 23.00%, about 23.10%, about 23.20%, about 23.30%, about 23.40%, about 23.50%, about 23.60%, about 23.70%, about 23.80%, about 23.90%, about 24.00%, about 24.10%, about 24.20%, about 24.30%, about 24.40%, about 24.50%, about 25.25%, about 20.30%, about 25.30%, about 25.25%, about 25.30%, about 25.25%, about 26%, about 25.30%, about 25.25%, about 25.30%, about 25%, about 25.25%, about 25%, about 25.30%, about 25%, about 25.30, About 26.50%, about 26.60%, about 26.70%, about 26.80%, about 26.90%, about 27.00%, about 27.10%, about 27.20%, about 27.30%, about 27.40%, about 27.50%, about 27.60%, about 27.70%, about 27.80%, about 27.90%, about 28.00%, about 28.10%, about 28.20%, about 28.30%, about 28.40%, about 28.50%, about 28.60%, about 28.70%, about 28.80%, about 28.90%, about 29.00%, about 29.10%, about 29.20%, about 29.30%, about 29.40%, about 29.50%, about 29.60%, about 29.70%, about 29.80%, about 29.90%, and about 30.00%.

In some embodiments, the weight% of sodium bicarbonate in the composition is between about 15% and about 25%. In some embodiments, the weight% 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 17.20%, about 17.30%, about 17.40%, about 17.50%, about 17.60%, about 17.70%, about 17.80%, about 17.90%, about 18.00%, about 18.10%, about 18.20%, about 18.30%, about 18.40%, about 18.50%, about 18.60%, about 18.70%, about 18.80%, about 18.90%, about 19.00%, about 19.10%, about 19.20%, about 20.20%, about 20.20.20%, about 20.20%, about 20%, about 20.20%, about 20%, about 20.20%, about 20%, about 20.20.20%, about 20%, about, About 21.50%, about 21.60%, about 21.70%, about 21.80%, about 21.90%, about 22.00%, about 22.10%, about 22.20%, about 22.30%, about 22.40%, about 22.50%, about 22.60%, about 22.70%, about 22.80%, about 22.90%, about 23.00%, about 23.10%, about 23.20%, about 23.30%, about 23.40%, about 23.50%, about 23.60%, about 23.70%, about 23.80%, about 23.90%, about 24.00%, about 24.10%, about 24.20%, about 24.30%, about 24.40%, about 24.50%, about 24.60%, about 24.70%, about 24.80%, about 24.90%, and about 25.00%.

In some embodiments, the weight% of citric acid in the composition is between about 5% and about 15%. In some embodiments, the weight% 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%, about 7.30%, about 7.40%, about 7.50%, about 7.60%, about 7.70%, about 7.80%, about 7.90%, about 8.00%, about 8.10%, about 8.20%, about 8.30%, about 8.40%, about 8.50%, about 8.60%, about 8.70%, about 8.80%, about 8.90%, about 9.00%, about 9.10%, about 9.20%, about 9.30%, about 9.20%, about 10.10%, about 10.30%, about 10%, about 10.30%, about 10.10%, about 10%, about 10.30%, about 10%, about 10.30%, about 10%, about 10.30%, about 10%, about 10.50%, about 10, About 11.50%, about 11.60%, about 11.70%, about 11.80%, about 11.90%, about 12.00%, about 12.10%, about 12.20%, about 12.30%, about 12.40%, about 12.50%, about 12.60%, about 12.70%, about 12.80%, about 12.90%, about 13.00%, about 13.10%, about 13.20%, about 13.30%, about 13.40%, about 13.50%, about 13.60%, about 13.70%, about 13.80%, about 13.90%, about 14.00%, about 14.10%, about 14.20%, about 14.30%, about 14.40%, about 14.50%, about 14.60%, about 14.70%, about 14.80%, about 14.90%, and about 15.00%.

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 polyvinylpyrrolidone. In some embodiments, the weight% of polyvinylpyrrolidone in the composition is selected from the group consisting of some embodiments, and the weight% 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 4.60%, about 4.70%, about 4.80%, about 4.90%, 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 7.00%, about 7.10%.

In some embodiments, the polyvinylpyrrolidone is crosslinked. In some embodiments, the weight% 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%.

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 mannitol. In some embodiments, the weight% 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%, about 8.00%, about 8.10%, about 8.20%, about 8.30%, about 8.40%, about 8.50%, about 8.60%, about 8.70%, about 8.80%, about 8.90%, about 9.00%, about 9.10%, about 9.20%, about 9.30%, about 9.20%, about 10.10%, about 10.30%, about 10%, about 10.30%, about 10.10%, about 10%, about 10.30%, about 10%, about 10.30%, about 10%, about 10.30%, about 10%, about 10.50%, about 10, About 11.50%, about 11.60%, about 11.70%, about 11.80%, about 11.90%, about 12.00%, about 12.10%, about 12.20%, about 12.30%, about 12.40%, about 12.50%, about 12.60%, about 12.70%, about 12.80%, about 12.90%, about 13.00%, about 13.10%, about 13.20%, about 13.30%, about 13.40%, about 13.50%, about 13.60%, about 13.70%, about 13.80%, about 13.90%, about 14.00%, about 14.10%, about 14.20%, about 14.30%, about 14.40%, about 14.50%, about 14.60%, about 14.70%, about 14.80%, about 14.90%, 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 15.90%, about 17.00%, about 16.60%, about 16.17.10%, about 16.20%, about 16.30%, about 17.30%, about 17.50%, about 16.60%, about 16.10%, about 16.20%, about 17.30%, about 16.10%, about 16.30%, about 17.30%, about 16.50%, about 16.60%, about 17.10%, about 16.10%, about 16.20%, about 17.30%, about 16%, about 17.10%, about 16%, about 17.30%, 17.10%, about 16%, about 16.30%, about 17.30%, about 18.00%, about 18.10%, about 18.20%, about 18.30%, about 18.40%, about 18.50%, about 18.60%, about 18.70%, about 18.80%, about 18.90%, about 19.00%, about 19.10%, about 19.20%, about 19.30%, about 19.40%, about 19.50%, about 19.60%, about 19.70%, about 19.80%, about 19.90%, and about 20.00%.

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 magnesium stearate. In some embodiments, the weight% of magnesium stearate in the composition is 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%, about 0.31%, about 0.32%, about 0.33%, about 0.34%, about 0.35%, about 0.36%, about 0.37%, about 0.38%, about 0.39%, about 0.40%, about 0.41%, about 0.32%, about 0.33%, about 0.34%, about 0.35%, about 0.36%, about 0.37%, about 0.38%, about 0.39%, about 0.40%, about 0.42%, about 0.46%, about 0.51%, about 0.46%, about 0.51%, about 0.46%, about 50%, about 0.51%, about 50%, about 0., About 0.60%, about 0.61%, about 0.62%, about 0.63%, about 0.64%, about 0.65%, about 0.66%, about 0.67%, about 0.68%, about 0.69%, about 0.70%, about 0.71%, about 0.72%, about 0.73%, about 0.74%, about 0.75%, about 0.76%, about 0.77%, about 0.78%, about 0.79%, about 0.80%, about 0.81%, about 0.82%, about 0.83%, about 0.84%, about 0.85%, about 0.86%, about 0.87%, about 0.88%, about 0.89%, about 0.90%, about 0.91%, about 0.92%, about 0.93%, about 0.94%, about 0.95%, about 0.96%, about 0.97%, about 0.98%, about 0.99%, about 1.00%, about 1.01%, about 1.02%, about 1.03%, about 1.04%, about 1.1.1.1%, about 1.1.1%, about 1.1.06%, about 1.1.1%, about 1.05%, about 1.1.1%, about 1%, about 1.06%, about 1.1%, about 1.1.1%, about 1.1%, about 1%, about 1.1%, about 1.1.1.05%, about 1%, about 1.1%, about 1%, about 1.1.1%, about 1%, about 1.1%, about 1, About 1.25%, about 1.26%, about 1.27%, about 1.28%, about 1.29%, about 1.30%, about 1.31%, about 1.32%, about 1.33%, about 1.34%, about 1.35%, about 1.36%, about 1.37%, about 1.38%, about 1.39%, about 1.40%, about 1.41%, about 1.42%, about 1.43%, about 1.44%, about 1.45%, about 1.46%, about 1.47%, about 1.48%, about 1.49%, about 1.50%, about 1.51%, about 1.52%, about 1.53%, about 1.54%, about 1.55%, about 1.56%, about 1.57%, about 1.58%, about 1.59%, about 1.60%, about 1.61%, about 1.62%, about 1.63%, about 1.64%, about 1.65%, about 1.66%, about 1.67%, about 1.68%, about 1.59%, about 1.60%, about 1.81%, about 1.80%, about 1.83%, about 1.82%, about 1.81%, about 1.82%, about 1.83%, about 1.82%, about 1.81%, about 1.83%, about 1.82%, about 1.81%, about 1.80%, about 1.83%, about 1.84%, about 1.83%, about 1.82%, about 1.83%, about 1.80%, about 1., About 1.90%, about 1.91%, about 1.92%, about 1.93%, about 1.94%, about 1.95%, about 1.96%, about 1.97%, about 1.98%, about 1.99%, and about 2.00%.

In one embodiment, the present 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 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340mg, about 345 mg, about 350 mg, about 355mg, about 360mg, about 365 mg, about 370 mg, about 375 mg, about 376mg, 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 425mg, about 430mg, about 435 mg, about 440 mg, about 445 mg and about 450 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 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340mg, about 345 mg, about 350 mg, about 355mg, about 360mg, about 365 mg, about 370 mg, about 375 mg, about 376mg, 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 425mg, about 430mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 378mg, 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 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220mg, about 225mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255mg, 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 340mg, about 345 mg, about 350 mg, about 261mg, about 264 mg, about 266 mg, and about 269 mg.

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

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

In some embodiments, the polyvinylpyrrolidone is crosslinked. In some embodiments, the amount of cross-linked polyvinylpyrrolidone in the dosage form is between about 25mg 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 25mg, about 30mg, about 35mg, about 40mg, about 43mg, about 45mg, about 50mg, about 52 mg, about 55mg, about 60mg, about 65mg, about 70 mg and about 75 mg.

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 50mg and about 300 mg. In some embodiments, the amount of mannitol in the dosage form is selected from the group consisting of: 50mg, about 55mg, about 60mg, about 65mg, about 70 mg, about 75mg, about 80mg, about 85 mg, about 90mg, about 95mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135mg, 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 180mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220mg, about 225mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255mg, 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 102mg, about 135mg, 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 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 3.15mg, 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, about 3.80 mg, about 3.85 mg, about 3.90mg, about 3.95 mg, about 4.00mg, about 4.05 mg, about 4.10 mg, about 4.15 mg, about 4.20 mg, about 4.25 mg, about 4.30 mg, about 4.90 mg, about 4.95 mg, about 4.00mg, about 4.05 mg, about 4.10 mg, about 4.15 mg, about 4.20 mg, about 4.25 mg, about 4.90 mg, about 4.45 mg, about 4.55 mg, about 4., About 5.10 mg, about 5.15 mg, about 5.20 mg, about 5.25 mg, about 5.30 mg, about 5.35 mg, about 5.40mg, about 5.45 mg, about 5.50 mg, about 5.55 mg, about 5.60 mg, about 5.65 mg, about 5.70 mg, about 5.75 mg, about 5.80 mg, about 5.85 mg, about 5.90 mg, about 5.95 mg, about 6.00 mg, about 6.05 mg, about 6.10 mg, about 6.15mg, about 6.20 mg, about 6.25 mg, about 6.30 mg, about 6.35 mg, about 6.40 mg, about 6.45 mg, about 6.50 mg, about 6.55 mg, about 6.60 mg, about 6.65 mg, about 6.70 mg, about 6.75 mg, about 6.80 mg, about 6.85 mg, about 6.90mg, about 6.50 mg, about 7.55 mg, about 7.60 mg, about 7.65 mg, about 7.70 mg, about 7.75 mg, about 7.80 mg, about 7.45 mg, about 7.70 mg, about 7.45 mg, about 7.60 mg, about 7.7.45 mg, about 7.70 mg, about 7.7.7.7.7.45 mg, About 7.90 mg, about 8.00 mg, about 8.10mg, about 8.20 mg, about 8.30 mg, about 8.40 mg, about 8.50 mg, about 8.60mg, about 8.70 mg, about 8.80 mg, about 8.90 mg, about 9.00 mg, about 9.10 mg, about 9.20 mg, about 9.30 mg, about 9.40 mg, about 9.50 mg, about 9.60 mg, about 9.70 mg, about 9.80 mg, about 9.90 mg, about 8.00 mg, about 8.10mg, about 8.20 mg, about 8.30 mg, about 8.40 mg, about 8.50 mg, about 8.60mg, about 8.70 mg, about 8.80 mg, about 8.90 mg, about 9.00 mg, about 9.25 mg, about 9.50 mg, about 9.75 mg, about 10.00 mg, about 10.70 mg, about 10.80 mg, about 13.00 mg, about 13.75 mg, about 13.00 mg, about 13.75 mg, about 9.00 mg, About 14.50 mg, about 14.75 mg, and about 15.00 mg.

Derivatives prepared using a eutectic composition of aspirin, citric acid, sodium bicarbonate, L-theanine according to embodiments of the present invention may be administered by the sublingual route.

The pharmaceutical composition according to the embodiment of the present invention may be prepared as an orally disintegrating tablet, an oral liquid, a fast dissolving agent, a granule, a wafer (film agent), a pill or a powder.

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

Co-crystals according to embodiments of the invention may be used to improve one or more physical properties, such as solubility, stability and dissolution rate, of a selected therapeutically or prophylactically active pharmaceutical ingredient.

The present invention is described in further detail by way of examples, but it is not intended to limit the scope of the present invention to only these examples. While specific embodiments of the invention have been shown and described in detail to illustrate the application of the principles of the invention, it will be understood that the invention may be embodied otherwise without departing from such principles.

Theanine co-crystals, including aspirin/theanine co-crystals, 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 by reference herein in their entireties.

Reference to the literature

Each of the above-cited references is incorporated herein in its entirety as if fully set forth herein.

Claims (50)

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

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

3. A sublingual formulation of co-crystal aspirin, citric acid, sodium bicarbonate, L-theanine, wherein said formulation bypasses hepatic first pass effects when a rapid onset of action is desired, with improved dissolution rate and bioavailability compared to the oral route of conventional aspirin.

4. A co-crystal aspirin, citric acid, sodium bicarbonate, L-theanine sublingual formulation with an expected significantly reduced median platelet aggregation inhibition time compared to the oral route of conventional aspirin.

5. A water soluble co-crystal product of acetylsalicylic acid with citric acid, sodium bicarbonate and L-theanine for sublingual administration for the treatment of acute myocardial infarction.

6. Eutectic compositions of drugs from a specific drug class with the α and β amino acid enantiomers, L-and D-isomers, D, L-racemic mixtures, S-and R-isomers, S, R-racemic mixtures, all rotamers, tautomers, salt forms and hydrates of theanine, wherein the N-substituted functional R₁A group [ C ]₄Or gamma-CH₂-C(O)—NR1]May contain straight, cyclic or branched alkyl groups and derivatives thereof; linear, cyclic or branched alkenyl groups and derivatives thereof; and aromatic groups (which may be aryl groups) and derivatives thereof, which constitute all analogue forms of theanine.

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

8. A dosage form comprising a composition comprising 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 an amount of powder.

10. A method of treating acute myocardial infarction in a subject in need thereof comprising administering to the subject a sublingual formulation of co-crystal aspirin, citric acid, sodium bicarbonate, and L-theanine.

11. The method of claim 10, wherein the aspirin, citric acid, sodium bicarbonate, L-theanine co-crystal is absorbed in the subject's bloodstream via the sublingual route and bypasses hepatic first pass effects.

12. The composition of claim 1, wherein the weight% of aspirin in the composition is between about 20% and about 30%.

13. The composition of claim 1, wherein the weight% 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 claim 1, wherein the weight% of L-theanine in the composition is between about 20% and about 30%.

15. The composition of claim 1, wherein the weight% 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 claim 1, wherein the weight% of sodium bicarbonate in the composition is between about 15% and about 25%.

17. The composition of claim 1, wherein the weight% 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 claim 1, wherein the weight% of citric acid in the composition is between about 5% and about 15%.

19. The composition of claim 1, wherein the weight% 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%.

20. The composition of claim 1, further comprising one or more of a binder, an emulsifier, and a disintegrant.

21. The composition of claim 1, further comprising between about 2.5% and about 7.5% by weight polyvinylpyrrolidone.

22. The composition of claim 21, wherein the weight% 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 claims 21 or 22, wherein the polyvinylpyrrolidone is crosslinked.

24. The composition of claim 23, wherein the weight% of crosslinked polyvinylpyrrolidone in the composition is selected from the group consisting of: about 3.1% and about 3.3%.

25. The composition of claim 1, further comprising a sugar alcohol.

26. The composition of claim 1, further comprising between about 5% and about 20.0% by weight mannitol.

27. The composition of claim 26, wherein the weight% of mannitol in the composition is selected from the group consisting of: about 7.4%, about 9.8%, about 16.5% and about 17.9%.

28. The composition of claim 1, further comprising a lubricant.

29. The composition of claim 1, further comprising between about 0.01% and about 2.0% by weight magnesium stearate.

30. The composition of claim 29, wherein the weight% of magnesium stearate in the composition is about 0.5%.

31. The dosage form of claim 8, wherein the amount of aspirin in the dosage form is between about 300 mg and about 450 mg.

32. The dosage form of claim 8, wherein the amount of aspirin in the dosage form is selected from the group consisting of: about 376mg, about 379 mg, and about 381 mg.

33. The dosage form of claim 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 claim 8, wherein the amount of L-theanine in the dosage form is selected from the group consisting of: about 378mg, about 379 mg and about 383 mg.

35. The dosage form of claim 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 claim 8, wherein the amount of sodium bicarbonate in the dosage form is selected from the group consisting of: about 261mg, about 264 mg, about 266 mg and about 269 mg.

37. The dosage form of claim 8, wherein the amount of citric acid in the dosage form is between about 75mg and about 200 mg.

38. The dosage form of claim 8, wherein the amount of citric acid in the dosage form is selected from the group consisting of: about 131mg, about 134 mg, about 136 mg and about 137 mg.

39. The dosage form of claim 8, further comprising one or more of a binder, an emulsifier, and a disintegrant.

40. The dosage form of claim 8, further comprising polyvinylpyrrolidone in an amount between about 50mg and about 100 mg.

41. The dosage form of claim 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 claims 40 or 41, wherein the polyvinylpyrrolidone is crosslinked.

43. The dosage form of claim 42, wherein the amount of cross-linked polyvinylpyrrolidone in the dosage form is between about 25mg and about 75 mg.

44. The dosage form of any one of claims 42 or 43, wherein the amount of crosslinked polyvinylpyrrolidone in the dosage form is selected from the group consisting of: about 43mg and about 52 mg.

45. The dosage form of claim 8, further comprising a sugar alcohol.

46. The dosage form of claim 8, further comprising mannitol in an amount between about 50mg and about 300 mg.

47. The dosage form of claim 46, wherein the amount of mannitol in the dosage form is selected from the group consisting of: about 102mg, about 135mg, about 258 mg and about 269 mg.

48. The dosage form of claim 8, further comprising a lubricant.

49. The dosage form of claim 8, further comprising magnesium stearate in an amount between about 2.5 mg and about 15 mg.

50. The dosage form of claim 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.