USOO9289438B2

(12) United States Patent (10) Patent No.: US 9.289,438 B2

Brittain et al. 45) Date of Patent: *Mar. 22,9 2016

(54) INTRAVENOUS FORMULATION WITH A613/616 (2006.01) WATER-SOLUBLE COCRYSTALS OF A63L/98 (2006.01) ACETYLSALCYLIC ACID AND THEANINE C07C 67/52 (2006.01) O O C07C 2.3L/22 (2006.01) (71) Applicants: Harry G. Brittain, Milford, NJ (US); A619/00 (2006.01) Philip V. Felice, Smithtown, NY (US) A6II 45/06 (2006.01) (72) Inventors: Harry G. Brittain, Milford, NJ (US); 469/14 (2006.01) Philip V. Felice, Smithtown, NY (US) (52) U.S. Cl. CPC ...... A6 IK3I/616 (2013.01); A61 K9/0019 (73) Assignee: THEAPRIN PHARMACEUTICALS (2013.01); A61 K9/14 (2013.01); A61 K31/198 INC. Hauppauge, NY (US) (2013.01); A61 K3I/60 (2013.01); A61K 45/06 (2013.01); C07C 67/52 (2013.01); C07C (*) Notice: Subject to any disclaimer, the term of this 231/22 (2013.01); C07B 2.200/13 (2013.01) patent is extended or adjusted under 35 (58) Field of Classification Search U.S.C. 154(b) by 154 days. None This patent is Subject to a terminal dis- See application file for complete search history. claimer. (56) References Cited (21) Appl. No.: 14/169,291 U.S. PATENT DOCUMENTS (22) Filed: Jan. 31, 2014 8,173,625 B2 * 5/2012 Brittain ...... A61K 31,198 514,165 (65) Prior Publication Data 8,304.404 B2 * 1 1/2012 Brittain ...... A61K 31,198 514,165 US 2014/0148418A1 May 29, 2014 * cited by examiner Related U.S. Application Data (60) Continuation of application No. 13/967,027, filed on Primary Examiner — Svetlana M Ivanova Aug. 14, 2013, now Pat. No. 8,685.948, which is a (74) Attorney, Agent, or Firm Notaro, Michalos & continuation of application No. 13/617,508, filed on Zaccaria P.C. Sep. 14, 2012, now abandoned, which is a division of application No. 13/440,693, filed on Apr. 5, 2012, now (57) ABSTRACT Pat. No. 8.304,404, which is a division of application A method of treating high grade temperature using a water No. 12/437,735, filed on May 8, 2009, now Pat. No. soluble cocrystal composition contains a quantity of acetyl 8,173,625. salicylic acid and a quantity of a theanine enantiomer selected from an alpha variant of theanine or a beta variant of theanine (51) Int. Cl. or other form of theanine. A6 IK3I/60 (2006.01) A6 IK3I/2 (2006.01) 16 Claims, 15 Drawing Sheets U.S. Patent Mar. 22, 2016 Sheet 1 of 15 US 9,289.438 B2

FIG. 1 Photomicrographs taken at two magnifications of the crystalline cocrystal product formed by acetylsalicylic acid and L-theanine.

..

100X U.S. Patent Mar. 22, 2016 Sheet 2 of 15 US 9,289.438 B2

FIG 2 Differential Scanning calorimetry thermogram of the cocrystal product formed by acetylsalicylic acid and L-theanine.

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-0.4 g s e -0.7 O L

-10

- 13

- 1.6

55 70 85 1 OO 115 130 145 Temperature (°C) U.S. Patent Mar. 22, 2016 Sheet 3 of 15 US 9,289.438 B2

FIG 3 X-ray powder diffraction pattern of the cocrystal product formed by acetylsalicylic acid and L-theanine.

1 OO

60

40

5 10 15 20 25 30 35 40 Scattering Angle(degrees 20) U.S. Patent Mar. 22, 2016 Sheet 4 of 15 US 9,289.438 B2

FIG 4 Infrared absorption spectrum of the cocrystal product formed by acetylsalicylic acid and L-theanine.

1 OO

60

40

O 6OO 1000 1400 1800 22OO 26OO 3OOO 34OO 38OO Wavenumber (cm) U.S. Patent Mar. 22, 2016 Sheet 5 Of 15 US 9,289.438 B2

FIG 5 Raman spectrum of the cocrystal product formed by acetylsalicylic acid and L theanine.

1 OO

60

250 5OO 750 1000 1250 1500 1750 Raman Shift (cm) U.S. Patent Mar. 22, 2016 Sheet 6 of 15 US 9,289.438 B2

FIG. 6 Photomicrographs taken at two magnifications of the crystalline cocrystal product formed by acetylsalicylic acid and D-theanine.

SS sS.

40X

100X U.S. Patent Mar. 22, 2016 Sheet 7 Of 15 US 9,289.438 B2

FIG 7 Differential scanning calorimetry thermogram of the cocrystal product formed by acetylsalicylic acid and D-theanine.

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-0.4 S a , 5 cus -10

-13

- 1.6

55 7O 85 1 OO 115 130 145 Temperature (°C) U.S. Patent Mar. 22, 2016 Sheet 8 of 15 US 9,289.438 B2

FIG. 8 X-ray powder diffraction pattern of the cocrystal product formed by acetylsalicylic acid and D-theanine.

1 OO

60

40

5 10 15 2O 25 30 35 40 Scattering Angle(degrees 20) U.S. Patent Mar. 22, 2016 Sheet 9 Of 15 US 9,289.438 B2

FIG 9 Infrared absorption spectrum of the cocrystal product formed by acetylsalicylic acid and D-theanine.

1 OO

60

40

O 600 1 OOO 1400 1800 2200 2600 3OOO 3400 3800 Wavenumber (cm) U.S. Patent Mar. 22, 2016 Sheet 10 of 15 US 9,289.438 B2

FIG. 10 Raman spectrum of the cocrystal product formed by acetylsalicylic acid and D theanine.

100

80

60

40

250 5OO 750 1000 1250 15OO 1750 Raman Shift (cm) U.S. Patent Mar. 22, 2016 Sheet 11 of 15 US 9,289.438 B2

FIG 11 Photomicrographs taken at two magnifications of the crystalline cocrystal product formed by acetylsalicylic acid and DL-theanine.

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100X

S& 8

S s

8 U.S. Patent Mar. 22, 2016 Sheet 12 of 15 US 9,289.438 B2

FIG. 12 Differential scanning calorimetry thermogram of the cocrystal product formed by acetylsalicylic acid and DL-theanine.

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15

-2.0

-2.5

-3.0 55 70 85 1 OO 115 130 145 Temperature (°C) U.S. Patent Mar. 22, 2016 Sheet 13 of 15 US 9,289.438 B2

FIG. 13 X-ray powder diffraction pattern of the cocrystal product formed by acetylsalicylic acid and DL-theanine.

100

80

60

40

5 10 15 2O 25 30 35 40 Scattering Angle(degrees 20) U.S. Patent Mar. 22, 2016 Sheet 14 of 15 US 9,289.438 B2

FIG. 14 Infrared absorption spectrum of the cocrystal product formed by acetylsalicylic acid and DL-theanine.

1 OO

80

60

40

O 6OO 1000 1400 1800 22OO 26OO 3OOO 34OO 3800 Wavenumber (cm) U.S. Patent Mar. 22, 2016 Sheet 15 Of 15 US 9,289.438 B2

FIG. 15 Raman spectrum of the cocrystal product formed by acetylsalicylic acid and DL theanine.

100

80

60

40

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250 500 750 1 OOO 1250 1500 1750 Raman Shift (cm) US 9,289,438 B2 1. 2 INTRAVENOUS FORMULATION WITH Control of the inflammatory process is regulated by a cas WATER-SOLUBLE COCRYSTALS OF cade of biomolecular mechanisms. These mechanisms occur ACETYLSALCYLIC ACID AND THEANINE via two pathways: the cyclooxygenase pathway, which results in the formation of prostaglandins, and the lipoxyge This application is a continuation of U.S. application Ser. 5 nase pathway, which results in the formation of leukotrienes. No. 13/967,027, filed Aug. 14, 2013, which is a continuation Non-steroid anti-inflammatory drugs (NSAID), like aspirin, of U.S. application Ser. No. 13/617,508, filed Sep. 14, 2012, function via the cyclooxygenase pathway. There are three which is a divisional of U.S. application Ser. No. 13/440,693, major human lipoxygenases. They differ in the position of the filed Apr. 5, 2012 and now U.S. Pat. No. 8,304.404 issued double bond on the arachidonic acid molecule. These human 10 lipoxygenases include the 5-, 12-, and 15-lipoxygenases, Nov. 6, 2012, which is a divisional of U.S. application Ser. which respectively catalyze the insertion of oxygen at the No. 12/437,735 filed May 8, 2009 and now U.S. Pat. No. C-5, C-12 and C-15 positions of arachidonic acid. The result 8,173,625 issued May 8, 2012, which are all incorporated ing leukotrienes and lipoxins provide signaling molecules herein by reference. associated with a variety of human diseases Such as asthma, 15 atherosclerosis, psoriasis and inflammatory bowel disease. FIELD OF THE INVENTION Leukotrienes and lipoxins, have been implicated as critical signaling molecules in a variety of cancers. 15-HLO has been The present invention relates to a novel method of admin shown to be a key biological agent in colorectal cancers, istering acetylsalicylic acid, more specifically to a novel while 12-HLO is involved in pancreatic, breast and prostate intravenous formulation, using a water-soluble cocrystal cancers. 5-HLO is up-regulated in prostate cancer and its product of acetylsalicylic acid and theanine that has a neutral inhibition abolishes all cell proliferation, inducing apoptosis. pH and provides enhanced Stability and bioactivity as com Tylenol accounts for most drug overdoses in the United pared to previously known water-soluble formulations of States and other Western countries. The hepatotoxicity of aspirin Tylenol (acetaminophen), statins (cholesterol lowering 25 drugs), antiretrovirals (taken for HIV and AIDS), and alcohol BACKGROUND OF THE INVENTION are well known. Researchers at Yale University have now provided new insight into the mechanism by which acetami Coronary artery disease is the leading cause of mortality in nophen causes liver damage in mice and determined that developed countries. In the United States, a heart attack aspirin provides Substantial protection from these toxic occurs approximately every 20 seconds. Aspirin inhibition of 30 effects of acetaminophen. Wajahat Z Mehal; Acetami cyclooxygenase has been shown to be beneficial in patients nophen—induced hepatotoxicity in mice is dependent on TIr'9 presenting with acute coronary syndrome and acute myocar and the Nalp3 Inflammasome, Journal of Clinical Investiga dial infarction. Researchers found that the median platelet tion; Jan. 26, 2009. inhibition times for chewed baby aspirin 324 mg. soluble Currently, intravenous aspirin is not approved for use in the aspirin (alka-Seltzer) 325 mg, and whole compressed non 35 United States. The poor solubility of aspirin in water and its enteric coated aspirin 324 mg, were 7.5 minutes, 7.5 minutes, rapid hydrolysis in the plasma to Salicylic acid and acetic acid and 10.0 minutes, respectively. Schwertner, et al., “Effects of have limited its intravenous use. different aspirin formulations on platelet aggregation times Attempts have been made in the past to produce an aspirin and on plasma salicylate concentration.” Thromb Res. 2006; product having an acceptable solubility, but none have proven 118(4): 529-34. Epub 2005 Nov. 18. Within 7.5 minutes, 40 to be totally satisfactory. though, an individual could be dead from one of a number of For example, the introduction of Bayer aspirin, as well as potentially fatal arrhythmias such as Ventricular tachycardia, Disprin (distributed in the United Kingdom), into water ventricular fibrillation or complete heart block. Early admin results in the formation of a cloudy Suspension indicative of istration of a novel intravenous aspirinformulation could start incomplete dissolution in water. Aspro Clear (distributed in benefitting the patient in a matter of seconds, whereas the full 45 Australia and New Zealand and marketed throughout benefit of traditional aspirin may not take effect until major Europe) imparts a non-cloudy, Snow globe effect in water for sequelae, complications or death has occurred. In a person more than three minutes after the tablets have effervesced. presenting with an acute myocardial infarction, intravenous It is well-known that lysine acetylsalicylate (sold as, e.g., aspirin is the preferred route for early platelet aggregation Aspegic and Aspisol) is suitable for intravenous administra inhibition. According to the American Heart Association’s 50 tion. The suitability of lysine for intravenous administration is 2007 National STEMI Statistics, 75% of the nations acute due to the formation of a salt of acetylsalicylic acid with a care hospitals are not capable of performing life-saving PCI basic amino acid, with the salt form exhibiting improved (Percutaneous Coronary Intervention) for STEMI (ST eleva solubility. Lysine acetylsalicylate, however, is not approved tion myocardial infarction) patients. As such, there is a clear by the FDA for use in the United States. See e.g., FDA unmet need for a novel intravenous aspirin with improved 55 Reports 2006-2008: Aspegic Side-Effect Report #5076936-8 pharmacokinetics and pharmacodynamics in patients pre (after drug was administered, patient developed cardio-respi senting with acute myocardial infarction. ratory arrest and ventricular fibrillation and died); FDA Aspirin inhibits prostanoid biosynthesis, in particular that Reports 2006-2008: Aspegic Side Effect Report #5379074-X of thromboxane A2 and prostaglandins PGE2 and PGI2. (after drug was administered, patient experienced angina pec Aspirin irreversibly inhibits platelet cyclooxygenase 1 60 toris and recovered). (COX-1) through acetylation of the amino acid serine at posi U.S. Pat. Nos. 5,665.388 and 5,723,453 to Phykitt, disclose tion 529, thereby preventing arachidonic acid access to the an essentially sodium-free, soluble alkaline aspirin com COX-1 catalytic site through steric hindrance. By inhibiting pound. The formulations disclosed in these references, how COX-1, the platelet is unable to synthesize prostaglandin H2, ever, Suffer from a number of disadvantages. One disadvan which would otherwise be converted to thromboxane A2, 65 tage is that the use of bicarbonates, as disclosed therein, which causes platelet aggregation, an early step in the coagul causes gas to be formed when ingested by patients. Another lation cascade. disadvantage is that the relatively high pH of the composi US 9,289,438 B2 3 4 tions disclosed therein (i.e., greater than 8.0) leads to rapid The amino acids glutamine and glutamic acid have com hydrolysis and instability of the drug Substance and, there mon molecular elements with theanine. Some examples of fore, a shortened shelf-life. common molecular elements are pl(isoelectric point), polar Many of the formulations disclosed in U.S. Pat. Nos. 5,157, ity, hydropathy index, and elements that Support their role as 030 and 5,776,431 to Galat are formed as two separate com metabolite targets for theanine. The overlapping molecular positions (mixture “A” and mixture “B”), which is disadvan properties allow theanine to function as a glutamine or tageous from manufacturing, packaging and use standpoints. glutamic acid analogue. These properties relate to the elec Furthermore, the formulations in these references are blended trostatic profile of theanine under physiological conditions and then directly added to water. There is no indication that and its overall structural geometry, which includes atoms the blended product is stable. Further, compositions formu 10 common to the related core amino acids glutamine and lated in accordance with the Galat patents take up to two to glutamic acid. The coincident array of atoms and the relative three minutes to substantially completely dissolve in water. electrostatic structure of glutamine and glutamic acid allow Compositions formulated in accordance with the methods them to serve as targets for theanine. The targets also include disclosed in Patent Application Publication No. 2006/ 15 the enzymes, proteins, receptors or other macromolecules 0292225 to Felix take up to 15-30 seconds to completely they effectively bind. In the case of glutamic acid, the atoms dissolve in water with stirring. that make up the isosteric structure up to the C5 or gamma Theanine, like aspirin, is known to have salutary effects. It carboxyl are in the same array as theanine. In the case of is found in ordinary tea leaves from Camellia sinensis and the glutamine, the isosteric and isoelectronic atoms of glutamine mushroom Xeroconus badius, but is otherwise rare in nature. are equal to theanine's where hydrogen has been replaced by Preliminary research, Suggests that L-theanine promotes ethyl (—CHs) on the carboxamide nitrogen of glutamine. alpha wave generation in the brain. Thereby, an awake, alert Glutathione is the liver's first-line defense against drugs and relaxed physical and mental condition is achieved, which and chemicals. It is used by cancer cells against drugs and demonstrates theanine's effectiveness in stress management. chemicals. Cancer cells use glutathione to detoxify doxoru L-theanine does not cause drowsiness or impair a person’s 25 bicin and escort the drug out of cells. Theanine is able to motor skills. It has been shown to work antagonistically interfere with this process due to its structural similarity to against the negative side effects of caffeine, to increase glutamate. Glutamic acid, or glutamate, is one of the compo dopamine and serotonin concentrations in the brain, to be nents of glutathione, the drug detoxifier. Because it looks like effective in reducing the hypertension and disturbance of glutamic acid, cancer cells take up and mistakenly use the sleep often associated with the use of caffeine, and to dimin 30 theanine to create glutathione. But the glutathione they create ish symptoms of premenstrual syndrome. Laboratory studies with theanine does not detoxify like natural glutathione. indicate that theanine produces these effects by increasing the Instead, this theanine-based glutathione appears to block the level of GABA (gamma-aminobutyric acid), an important ability of cancer cells to detoxify. inhibitory neurotransmitter in the brain. Further, in addition to enhancing doxorubicin’s cancer It has been reported that theanine Supports the immune 35 killing effects without harming healthy tissue, theanine also system and may reduce plasma total cholesterol, cholesterol keeps doxorubicin out of healthy tissue. This is a major added ester and very-low-density lipoprotein cholesterol. benefit, since one of the drawbacks of the use of doxorubicin Studies on the effects of theanine on alcohol metabolism is its toxicity to the heart. The potential of theanine as an and hepatic toxicity have shown that theanine is effective adjunct to cancer chemotherapy was proposed by researcher against alcoholic liver injury. 40 Yasuyuki Sadzuka, who confirmed that theanine, a major Theanine also has the potential to protect neurons from amino acid in green tea, enhances the antitumor activity of excesses of glutamate. Glutamate is an essential brain chemi doxorubicin (DOX) without an increase in DOX-induced side cal that may be released in excess amounts with some disease effects. He postulated that the action of theanine is due to conditions (e.g., amyotrophic lateral Sclerosis and cere decreases in glutamate uptake via inhibition of the glutamate brovascular dementia) and with brain injuries, as occurs with 45 transporter and reduction of glutathione and DOX export strokes or physical injuries. Theanine may protect against this from the cell. Theanine enhances the antitumor activity not damage by blocking glutamine entrance to cells due to the only of DOX but also of cisplatin and irinotecan (CPT-11). In similarity in the stereochemical structures of theanine and essence, Sadzuka found that theanine could block the export glutamine. of doxorubicin (Adriamycin) from cancer cells by blocking A direct metabolite of amino acidsglutamine and glutamic 50 the glutamate and glutathione transporter mechanisms; the acid, theanine is made different by its ethyl-N-alkylation of elevated level of the drug within cancer cells strongly inhibits glutamine's nitrogen. The amino acid scaffolds glutamine the tumor. Sadzuka Y, et al., “The effects of theanine, as a and its metabolite glutamic acid provide the general, alpha novel biochemical modulator, on the antitumor activity of amino acid core structure responsible for theanine's trans adriamycin.” Cancer Letters 1996; 105(2): 203-209; Sadzuka port, while ethyl-N-alkylation of glutamine provides both its 55 Y, et al., “Modulation of cancer chemotherapy by green tea. transport and pharmacological properties. The similarity of Clinical Cancer Research 1998; 4(1): 153-156; SadzukaY, et glutamine's and glutamic acids structure with theanine al., “Efficacies of tea components on doxorubicin induced allows theanine to be substrate and product competitors for all antitumor activity and reversal of multidrug resistance. Toxi physiological glutamine and glutamic acid reactions, provid cology Letters 2000: 114 (1-3): 155-162; Sadzuka Y, et al., ing their charges are similar. Therefore, wherever glutamine 60 “Improvement of idarubicin induced antitumor activity and or glutamic acid is a metabolite, theanine can activate, inhibit bone marrow Suppression by theanine, a component of tea. or add to target activity. This is why its effects are so far Cancer Letters 2000: 158(2): 119-24: Sadzuka Y, et al., reaching. It is a glutamine mimetic with pharmacological “Enhancement of the activity of doxorubicin by inhibition of activity. Glutamine is a significant consumer of ATP for nitro glutamate transporter. Toxicology Letters 2001: 123 (2-3): gen incorporation, which may explain some of the anti-cancer 65 159-67: Sadzuka Y, et al., “Effect of dihydrokainate on the and anti-HIV activity of theanine. If N-fixation is inhibited, antitumor activity of doxorubicin. Cancer Letters 2002; 179 cell or viral structure growth is also inhibited. (2): 157-163. US 9,289,438 B2 5 6 Therapeutic compounds, such as aspirin, are most stable in venous administration having the above characteristics and a crystalline form, but can display poor aqueous solubilities which allow for delivery of therapeutic quantities of theanine and slow dissolution rates. These properties impart the ten to the bloodstream. dency to reduce the bioavailability of the active pharmaceu These and other objects of the present invention are tical ingredient (API), thereby slowing absorption. achieved in accordance with one embodiment of the present A cocrystal is a multiple-component crystal, in which two invention by provision of a water-soluble aspirin-theanine or more molecules associate (but do not bond) on the molecu cocrystal composition which includes a quantity of acetyl lar level in solid crystalline form under ambient conditions. salicylic acid and a quantity of a theanine enantiomer associ They are attractive to the pharmaceutical industry because ated with the quantity of acetylsalicylic acid, the cocrystal they offer opportunities to modify the chemical and/or physi 10 composition being formed by physically combining the quan cal properties of an API without the need to make or break tity of acetylsalicylic acid and the quantity of a theanine covalent bonds. In pharmaceutical cocrystals, the molecular enantiomer into a mixture and wetting the mixture with a structure of the API is not changed. This has important impli quantity of a wetting agent and grinding the combination for cations for streamlined regulatory approval of new forms. By a length of time sufficient to produce a dried-crystalline mass. their very nature, APIs, molecules that contain exterior hydro 15 In some embodiments, the wetting agent employed is metha gen-bonding moieties, are predisposed to formation of coc nol. rystals. Pharmaceutical cocrystals will afford forms of APIs Formulations according to embodiments of the present with improved physical properties Such as Solubility, stability, invention protect aspirin from hydrolysis, with the bulk active hygroscopicity, and dissolution rate. Physical properties are ingredient being a well-defined, free-flowing crystalline solid not just dependent upon molecular structure. They are also which has enhanced stability and bioactivity. The solid has a critically dependent upon Supramolecular chemistry and its solubility in water of about 10 mg/mL, and yields a clear influence upon crystal structure. The application of the con aspirin solution shortly after being mixed. cepts of Supramolecular synthesis and crystal engineering to Compositions according to embodiments of the present the development of pharmaceutical cocrystals offers many invention are very soluble in water, requiring about less than opportunities related to drug development and delivery. 25 one part water per part Solute, especially when compared to Thus, a water-soluble aspirin-theanine cocrystal composi traditional aspirin, which is only very slightly soluble, requir tion which has enhanced stability and bioactivity as compared ing about 1,000 to 10,000 parts water per part solute. to previously-known, water-soluble analgesic compositions, In accordance with an embodiment of the present inven and which delivers the salutary effects of both aspirin and tion, a method of creating a water-soluble aspirin-theanine theanine, is needed. 30 cocrystal composition includes the steps of (i) providing a The present invention satisfies these and other medical quantity of acetylsalicylic acid; adding a quantity of a thean needs and overcomes deficiencies found in the prior art. ine enantiomer to the quantity of acetylsalicylic acid to form a mixture comprising the quantity of acetylsalicylic acid and SUMMARY OF THE INVENTION the enantiomer of theanine; (ii) wetting the mixture; and (iii) 35 grinding the mixture for a length of time Sufficient to produce Accordingly, it is an object of the present invention to a dried crystalline mass. In certain of these embodiments, provide a water-soluble aspirin-theanine cocrystal composi methanol is employed in the step of wetting the mixture. In tion having a crystalline structure and which has enhanced certain of these embodiments, the dried crystalline mass has stability and bioactivity, as compared to previously-known, an aqueous solubility of at least about 9.0 mg/mL. water-soluble analgesic compositions. 40 In some embodiments of the present invention the quantity A further object of the present invention is to provide a of acetylsalicylic acid falls within the range of about 5% to water-soluble aspirin-theanine cocrystal composition having 95% by weight of the mixture of the quantity of acetylsali the above characteristics and which is rapidly water-soluble. cylic acid and the quantity of a theanine enantiomer. In other Yet a further object of the present invention is to provide a embodiments, the quantity of acetylsalicylic acid falls within water-soluble aspirin-theanine cocrystal composition having 45 the range of about 15% to 85% by weight of the mixture of the the above characteristics and which may be used in the rela quantity of acetylsalicylic acid and the quantity of a theanine tively large dosages that are required for anti-inflammatory enantiomer. In further embodiments, the quantity of acetyl treatment. salicylic acid is about 50% by weight of the mixture of the It is an object of the present invention to provide a method quantity of acetylsalicylic acid and the quantity of a theanine of administering a water-soluble aspirin-theanine cocrystal 50 enantiomer. composition intravenously in humans that has a neutral pH, In some of these embodiments, the theanine enantiomer is provides enhanced stability and bioactivity, and is suitable for the L-form. In other embodiments, the theanine enantiomer is treatment of various diseases and medical conditions. the D-form. In further embodiments, the theanine enantiomer Still another object of the present invention is to provide is the DL-form. aqueous aspirin-theanine cocrystal formulations Suitable for 55 In some of these embodiments, the resultant aspirin-thea intravenous administration having the above characteristics nine cocrystal composition is dissolved in a solvent to forman and which allow for rapid delivery of acetylsalicylic acid to aspirin-theanine cocrystal Solution. In certain of these the bloodstream. embodiments, the solventis water. In certain of these embodi Yet a further object of the present invention is to provide ments, the resultant aspirin-theanine cocrystal solution has a aqueous aspirin-theanine cocrystal formulations Suitable for 60 pH that is physiologic. In certain of these embodiments, the intravenous administration having the above characteristics resultant aspirin-theanine cocrystal Solution has a pH in the and which may be used for extended periods of time without range of about 7.35 to about 7.45. In certain of these embodi causing the gastrointestinal upset and/or erosions, bleeding, ments, the resultant aspirin-theanine cocrystal solution has a or perforation of the gastrointestinal tract which may occur pH which is about 7.4. with conventional oral aspirin. 65 In accordance with another embodiment of the present Another object of the present invention is to provide aque invention, a method of creating a water-soluble aspirin-thea ous aspirin-theanine cocrystal formulations Suitable for intra nine cocrystal composition includes the steps of: (i) providing US 9,289,438 B2 7 8 a quantity of acetylsalicylic acid; (ii) adding a quantity of an FIG. 10 is a Raman spectrum of the cocrystal formed by enantiomer of theanine to said quantity of acetylsalicylic acid acetylsalicylic acid and D-theanine according to embodi to form a mixture comprising said quantity of acetylsalicylic ments of the present invention; acid and said enantiomer of theanine; (iii) dissolving said FIG. 11 depicts photomicrographs taken at two magnifica combination in a quantity of a solvent to form a solution; and tions of the crystalline cocrystal product formed by acetyl (iv) drying said solution for a length of time sufficient to salicylic acid and DL-theanine; produce a dried crystalline mass. In certain of these embodi FIG. 12 is a differential scanning calorimetry thermogram ments, the dried crystalline mass has an aqueous solubility of of the cocrystal formed by acetylsalicylic acid and DL-thea at least about 9.4 mg/mL. In certain of these embodiments, nine according to embodiments of the present invention; water is employed as the solvent. In certain of these embodi 10 FIG. 13 is an X-ray powder diffraction pattern of the coc ments, the drying step is performed by means of a rotary rystal formed by acetylsalicylic acid and DL-theanine evaporation process. according to embodiments of the present invention; In certain of these embodiments, the theanine enantiomer FIG. 14 is an infrared absorption spectrum of the cocrystal is the L-form. In some of these embodiments the theanine formed by acetylsalicylic acid and DL-theanine according to 15 embodiments of the present invention; and enantiomer is the D-form. In further of these embodiments, FIG. 15 is a Raman spectrum of the cocrystal formed by the theanine enantiomer is the DL-form. acetylsalicylic acid and DL-theanine according to embodi In some embodiments of the present invention, the thean ments of the present invention. ine enantiomer further comprises a functional group thereon. In these embodiments, the carbohydrate func DESCRIPTION OF THE PREFERRED tional group may be of the L-configuration or the D-configu EMBODIMENTS ration. In these embodiments, the employed may be , , , oli The present invention satisfies needs left unresolved by the gosaccharides or . prior art by providing a method for synthesizing a soluble In some embodiments of the present invention, the thean 25 cocrystal formed by acetylsalicylic acid and L-theanine ine enantiomer further comprises an amino acid functional which is readily administerable to individuals through a vari group thereon. In certain of these embodiments, the amino ety of media. acid functional group is a dipeptide. Embodiments of the present invention employ L-theanine, The various features of novelty which characterize the a rare amino acid. L-theanine is a water-soluble, white crys invention are pointed out with particularity in the claims 30 talline powder, having a Chemical Abstracts Service (CAS) annexed to and forming a part of this disclosure. For a better Registry Number of 3081-61-6 and a GRAS classification understanding of the invention, its operating advantages and (GRAS Notice Number: GRN 000209). L-theanine has the specific objects attained by its uses, reference is made to the empirical formula C2HNO, a molecular weight of accompanying figures and descriptive matter in which a pre 174.20, and the systematic name of 2-Amino-4-(ethylcar ferred embodiment of the invention is illustrated. 35 bamoyl)butyric acid. Being 5-N-ethyl glutamine, theanine differs from glutamine by the CH2-CH3 (ethyl) group (re BRIEF DESCRIPTION OF THE DRAWINGS placing hydrogen). N-Ethyl confers on theanine its active properties. In the drawings: Embodiments of the present invention include cocrystals FIG. 1 depicts photomicrographs taken at two magnifica 40 of acetylsalicylic acid with theanine (5-N-ethyl-glutamine). tions of the crystalline cocrystal product formed by acetyl Further, the theanine contained in compositions according to salicylic acid and L-theanine according to embodiments of embodiments of the present invention may be of any of the present invention; L-form, D-form, DL-form. FIG.2 is a differential scanning calorimetry thermogram of Embodiments of the present invention may include the the cocrystal formed by acetylsalicylic acid and L-theanine 45 amino acid scaffolds glutamine and/or glutamic acid. according to embodiments of the present invention; Non-limiting examples of enantiomers utilized in embodi FIG. 3 is an X-ray powder diffraction pattern of the cocrys ments according to the present invention may include a tal formed by acetylsalicylic acid and L-theanine according to D-enantiomer of Theanine, D-GlucNHEt)-OH, 2R enanti embodiments of the present invention: omer; an L-enantiomer of Theanine, L-Glu(NHEt)-OH, 2R FIG. 4 is an infrared absorption spectrum of the cocrystal 50 enantiomer; a DL enantiomer of Theanine, DL-GlucNHEt)- formed by acetylsalicylic acid and L-theanine according to OH enantiomer; a D-enantiomer of Theanine, D-Gln(Et)- embodiments of the present invention: OH, 2R enantiomer; an L-enantiomer of theanine, L-Gln(Et)- FIG. 5 is a Raman spectrum of the cocrystal formed by OH, 2R enantiomer; and a DL-enantiomer of theanine, acetylsalicylic acid and L-theanine according to embodi DL-Gln(Et)-OH, 2R enantiomer. The purity percentages of ments of the present invention; 55 the D-enantiomers of theanine, D-GlucNHEt)-OH, 2R enan FIG. 6 depicts photomicrographs taken at two magnifica tiomer and D-Gln(Et)-OH, 2R enantiomer; the Lenantiomers tions of the crystalline cocrystal product formed by acetyl of theanine, L-GlucNHEt)-OH, 2R enantiomer and L-Gln salicylic acid and D-theanine; (Et)-OH, 2R enantiomer; and the DL-enantiomers of thean FIG. 7 is a differential scanning calorimetry thermogram of ine, DL-GlucNHEt)-OH, 2R enantiomer and DL-Gln(Et)- the cocrystal formed by acetylsalicylic acid and D-theanine 60 OH, 2R enantiomer in compositions according to according to embodiments of the present invention; embodiments of the present invention is 99--%; 99--%. 2R FIG. 8 is an X-ray powder diffraction pattern of the cocrys enantiomer. The D-enantiomer at 99-96: 99--% ee.9% (2R) is tal formed by acetylsalicylic acid and D-theanine according where the first measure is the overall chemical purity (hplc) to embodiments of the present invention; and where the second measure is ee % (2R) known as the FIG. 9 is an infrared absorption spectrum of the cocrystal 65 "percent enantiomeric excess.” The % ee is the measure of formed by acetylsalicylic acid and D-theanine according to chiral purity equal to % R-% S/% R* 100 defined by the embodiments of the present invention: ratios of their diasteriomeric derivatives. Purity percentages US 9,289,438 B2 9 10 may range from 90% to 99.99% in any D or L configuration The effective amount of acetylsalicylic acid administered of any theanine or any enantiomer thereof. to a patient (i.e., the amount that will have a salutary effect Embodiments of the present invention may include cocrys with regards to a disease or condition being treated) will be tal compositions of acetylsalicylic acid and alpha variants of influenced by gender, age, weight, body fluid status, severity L-theanine, acetylsalicylic acid and alpha variants of D-thea 5 of the disease or condition being treated, liver enzyme func nine, and acetylsalicylic acid and alpha variants of DL-thea tion, and renal excretion of salicylate which, in turn, is depen nine. dent upon urine pH, and protein binding of salicylates, which Non-limiting examples of alpha variants used in embodi is concentration-dependent. ments according to the present invention may include The term “carbohydrate as it is used herein, generally L-northeanine, D-northeanine, DL-northeanine, L-homoth 10 refers to simple organic compounds that are aldehydes or eanine, D-homotheanine, DL-homotheanine L-bishomothea ketones substituted with multiple hydroxyl groups, of the nine, D-bishomotheanine, and DL-bishomotheanine, i.e., the general formula (CHO), where n is any number of three or respective C-1, C+1, and C+2 homologous analogues of thea greater. nine. 15 Monosaccharides, disaccharides, trisaccharides, oligosac According to embodiments of the present invention the L-, charides, polysaccharides, dipeptides, and combinations of D-, DL-alpha amino acids of theanine and their side-chain these may be used with the acetylsalicylic acid—theanine carbon homologues (nor, homo, and bishomologues) may cocrystal compositions according to embodiments of the have a functional R-group, where R1 may contain linear, present invention, in particular, with those cocrystals formed cyclic, or branched alkyl groups and derivatives thereof; lin according to the steps applied in Examples 1-8 below. ear, cyclic, or branched alkenyl groups and derivatives Compositions according to embodiments of the present thereof, and aromatic radicals and derivatives thereof. In invention may contain the theanderose (G6-O- embodiments of the present invention, the aromatic radicals glucosyl ), a Substance found specifically in honey. may be aryl radicals. Non-limiting examples of other natural that may be According to the embodiments of the present invention the 25 used in embodiments of the present invention include abequ single enantiomers (S and R) and racemic forms (S. R-mix ose, , allulose, , apiose, , beet oligosac ture) of the beta amino acids of theanine may have a func charides, bifurcose, , dextrose(D-), tional R-group, where R1 may contain linear, cyclic, or erlose, , , (levulose), , branched alkyl groups and derivatives thereof; linear, cyclic, fuculose, , gentiobiose, gentiotriose, gentiotetraose, or branched alkenyl groups and derivatives thereof, and aro 30 etc., , hamamelose, inulobiose, inulotriose, inulotet matic radicals and derivatives thereof. In embodiments of the raose, , isomaltotriose, isomaltotetraose, isomal present invention, the aromatic radicals may be aryl radicals. topentaose, (palatinose), kestose, kojibiose, lac Embodiments of the present invention may include cocrys tose, , laminaribiose, , , , tal compositions of acetylsalicylic acid and the enantiomers, , maltotetraose, etc., maltulose, meletzitose, meli L- and D-isomers, D, L-racemic mixture. S- and R-isomers, 35 biose, methose, , nystose, panose, paratose, pri S. R-racemic mixtures, all rotamers, tautomers, salt forms, meverose, , , , , , ruti and hydrates of the alpha and beta amino acids of theanine in nose, Sorbinose, , soybean , which the N-substituted functional R1-group C4 or gamma , Sucrose, , , theanderose, , tre CH2—C(O) NR1 may contain linear, cyclic, or branched halose, , Xylobiose, Xylotriose, etc., , or Xylu alkyl groups and derivatives thereof linear, cyclic, or 40 lose, all of which may be used with acetylsalicylic acid in branched alkenyl groups and derivatives thereof, and aro compositions according to embodiments of the present inven matic radicals and derivatives thereof making up all the ana tion. The carbohydrates used in embodiments of the present logue forms of theanine. In embodiments of the present invention may be of their respective D- or L-configurations. invention, the aromatic radicals may be aryl radicals. In certain embodiments, non-limiting examples of An aqueous solution is a solution in which water is the 45 alcohols that may be used include allitol, arabitol, erythritol, dissolving medium or solvent, and which is essentially free of galactitol, glycerol, glycol, iditol, inositol, isomalt, lactitol, colloidal solids. Dissolved crystals form true solutions and maltotetraol, maltotriol, mannitol, ribitol, sorbitol, talitol, are capable of passing through a semi-permeable membrane threitol, and Xylitol. The Sugar alcohols used in embodiments as in dialysis, whereas colloids are unable to pass through a according to the present invention may be of their respective semi-permeable membrane. The compositions according to 50 the D- or L-configurations. These Sugar alcohols have the embodiments of the present invention form a true solution benefits of having low glycemic indices. Mannitol, for when dissolved in water, are able to pass through a semi example, has been used to treat increased intracranial pres permeable membrane, and can be used in dialysis. Examples sure. The following crystalloids may be used in formulations of aqueous solutions that may be used in embodiments of the according to embodiments of the present invention: D5W. present invention include pure water, and the following: 55 D10W, D50, D5 0.3% NS, D5 0.45% NS, 0.45% NS, D5 D5W, D10W, D50, D5 0.3% NS, D5 0.45% NS, 0.45% NS, 0.9% NS, 0.9% NS, 3% NaCl, D5RL, LR, NaHCO, and D5 0.9% NS, 0.9% NS, 3% NaCl, D5RL, LR, NaHCO, and Xylitol solutions. Xylitol solutions. Formulations according to embodiments of the present Solutions formed by dissolving acetylsalicylic acid-thean invention may be fully dissolved in an aqueous Solution and ine cocrystal compositions according to embodiments of the 60 administered via the parenteral route. The following infusion present invention in water do not contain colloidal particles, fluids may be used informulations according to embodiments and hence, do not exhibit the strong Tyndall effect character of the present invention: D5W, D10W, D50, D50.3% NS, D5 istic of colloidal dispersions. 0.45% NS, 0.45% NS, D5 0.9% NS, 0.9% NS, 3% NaCl, It should be understood that the term "suitable, as it is used D5RL, LR, NaHCO3, and Xylitol solutions. herein, generally refers to the fact that the solution can be 65 Next, the present invention will be described in further administered intravenously to humans, without causing unfa detail by means of examples, without intending to limit the vorable side effects. Scope of the present invention to these examples alone. The US 9,289,438 B2 11 12 following are exemplary formulations of water-soluble ace D-theanine, and transferring the Solids to an agate mortar. The tylsalicylic acid compositions in accordance with the present solids were wetted with 500LL of methanol, and handground invention. with a pestle until a dried crystalline mass was obtained. Representative photomicrographs of the cocrystal product EXAMPLE1 are shown in FIG. 6 This product was characterized using differential scanning calorimetry (DSC; see FIG. 7), X-ray A cocrystal product of the present invention was prepared powder diffraction (XRPD; see FIG. 8), Fourier-transform by weighing 352 mg of acetylsalicylic acid and 340 mg of infrared spectroscopy with attenuated total reflectance sam L-theanine, and transferring the solids to an agate mortar. The pling (FTIR-ATR; see FIG.9), and Raman spectroscopy with solids were wetted with 500 uL of methanol, and hand 10 diffuse reflectance sampling (RAM-DR; see FIG. 10). In ground with a pestle until a dried crystalline mass was addition, 68 mg of the cocrystal product was found to dissolve obtained. This product was characterized using differential in 7.5 mL of water, making the aqueous solubility approxi scanning calorimetry (“DSC: see FIG. 2), x-ray powder mately 9 mg/mL. diffraction (XRPD;” see FIG.3), Fourier-transform infrared spectroscopy with attenuated total reflectance sampling 15 EXAMPLE 6 (“FTIR-ATR; see FIG. 4), and Raman spectroscopy with diffuse reflectance sampling (“RAM-DR;” see FIG. 5). In 363 mg of acetylsalicylic acid and 354 mg of D-theanine addition, 117 mg of the cocrystal product was found to dis were weighed into a 150 mL beaker, and dissolved in 100 mL Solve in 13 mL of water, making the aqueous solubility of water. The resulting clear Solution was then dried using approximately 9 mg/mL. rotatory evaporation until a dried crystalline mass was obtained. The DSC thermogram of this solid product is EXAMPLE 2 reflected in FIG. 7, the XRPD pattern is reflected in FIG. 8, the FTIR-ATR spectrum is reflected in FIG.9, and the RAM The aqueous solution formed in Example 1 was poured in DR spectrum is reflected in FIG. 10. an evaporating dish, and allowed to dry completely. The DSC 25 thermogram of the solid product is reflected in FIG. 2, the EXAMPLE 7 XRPD pattern is reflected in FIG.3, the FTIR-ATR spectrum is reflected in FIG. 4, and the RAM-DR spectrum is reflected A cocrystal product of the present invention was prepared in FIG. 5. by weighing 368 mg of acetylsalicylic acid, 179 mg of 30 L-theanine, and 178 mg of D-theanine, and transferring the EXAMPLE 3 solids to an agate mortar. The solids were wetted with 500 uL of methanol, and hand ground with a pestle until a dried 1.721 g of acetylsalicylic acid and 1.667 g of L-theanine crystalline mass was obtained. Representative photomicro were weighed and transferred into a large glass mortar. The graphs of the cocrystal product are shown in FIG. 11. This solids were wetted with 20 mL of methanol, and hand-ground 35 product was characterized using differential scanning calo with a pestle until a dried crystalline mass was obtained. The rimetry (DSC; see FIG. 12), x-ray powder diffraction (XRPD; DSC thermogram of the solid product is reflected in FIG. 2, see FIG. 13), Fourier-transform infrared spectroscopy with the XRPD pattern is reflected in FIG. 3, the FTIR-ATR spec attenuated total reflectance sampling (FTIR-ATR; see FIG. trum is reflected in FIG. 4, and the RAM-DR spectrum is 14), and Raman spectroscopy with diffuse reflectance sam reflected in FIG. 5.752 mg of the cocrystal product was found 40 pling (RAM-DR; see FIG. 15). In addition, 67 mg of the to dissolve in 80 mL of water, making the aqueous solubility cocrystal product was found to dissolve in 9.5 mL of water, 9.4 mg/mL. making the aqueous solubility approximately 7 mg/mL. Aliquots of the aqueous solution were separately diluted in 1:1 v/v ratios with (a) pH 7.4 tromethamine buffer, (b) 0.9% EXAMPLE 8 saline solution, (c) 7.5% sodium bicarbonate solution, (d) 5% 45 dextrose for injection, and (e) 50% dextrose for injection. The 358 mg of acetylsalicylic acid, 175 mg of L-theanine, and Solutions were observed to remain physically unchanged over 174 mg of D-theanine were weighed into a 150-mL beaker, a six-day period, indicating compatibility of the cocrystal and dissolved in 100 mL of water. The resulting clear solution product with each of the infusion solutions. was then dried using rotatory evaporation until a dried crys 50 talline mass was obtained. The DSC thermogram of this solid EXAMPLE 4 product is reflected in FIG. 12, the XRPD pattern is reflected in FIG. 13, the FTIR-ATR spectrum is reflected in FIG. 14, 435 mg of acetylsalicylic acid and 424 mg of L-theanine and the RAM-DR spectrum is reflected in FIG. 15. were weighed into a 200 mL round-bottomed flask, and dis The Tyndall effect is observed when particles of a solidare solved in 100 mL of water. The resulting clear solution was 55 dispersed in water but not dissolved. Such an effect is strongly then dried using rotatory evaporation until a dried crystalline observed in dispersions of Bayer aspirin, Disprin, and Aspro mass was obtained. The DSC thermogram of this solid prod Clear. No such strong effect is observed in water, or when uct is reflected in FIG. 2, theXRPD patternis reflected in FIG. cocrystal compositions according to embodiments of the 3, the FTIR-ATR spectrum is reflected in FIG. 4, and the present invention are dissolved in water. Colloids are particles RAM-DR spectrum is reflected in FIG. 5. 752 mg of the 60 which range in size from 1-1000 nm, and a Tyndall effect is cocrystal product was found to dissolve in 80 mL of water, created when a laser beam is scattered by its passage through making the aqueous solubility 9.4 mg/mL. a colloidal dispersion of non-dissolved particles. For such dispersions, the illumination of a visible path through the EXAMPLE 5 colloidal dispersion is observable. A true Solution, such as 65 water or a composition according to embodiments of the A cocrystal product of the present invention was prepared present invention dissolved in water, does not contain colloi by weighing 353 mg of acetylsalicylic acid and 341 mg of dal particles, and hence does not exhibit a strong Tyndall US 9,289,438 B2 13 14 effect characteristic of colloidal dispersions. These findings, An investigation regarding the degree of insoluble Sub detailed below, as well as the preceding examples, demon stance remaining after performance of the Tyndall effect strate that compositions according to embodiments of the experiment was carried out. The dispersions in the beakers present invention dissolve to form true Solutions in water, and were stirred to collect any undissolved solid in the center. An do not merely disperse to form a colloidal dispersion. 5 accumulation ofundissolved solid formed at the bottom of the Bayer aspirin beaker, but not in the beaker containing aspirin: Tyndall Experiment 1 (L)-theanine cocrystal product which displayed a crystal clear Solution. Comparison of Aspirin: (L)-Theanine Cocrystal Product with Disprin 10 Tyndall Effect Experiment 4 300 mg of the aspirin: (L)-theanine cocrystal product was Comparison of Aspirin: (L)-Theanine Cocrystal dissolved in 150 ml of water in one beaker and a 325 mg tablet Product with Water of Disprin was dispersed in 150 ml of water in another beaker. A 514 nm laser beam was first passed through the aspirin: 15 300 mg of the aspirin: (L)-theanine cocrystal product was (L)-theanine cocrystal solution and then through the Disprin dissolved in 150 ml of water in one beaker and 150 ml of water alone was place in another beaker. A514 nm laser beam dispersion. A strong Tyndall effect was observed in the aque was first passed through the aspirin: (L)-theanine cocrystal ous dispersion of Disprin, but was not observed with the solution and then through the water. A strong Tyndall effect composition according to the present invention dissolved in was not observed with water, nor was it observed with the Water. composition according to the present invention dissolved in An investigation regarding the degree of insoluble Sub water. Both water and the aspirin: (L)-theanine cocrystal stance remaining after performance of the Tyndall effect product exhibited crystal-clear solutions and were indistin experiment was carried out. The dispersions in the beakers guishable from one other. were stirred to collect any undissolved solid in the center. An 25 An investigation regarding the degree of insoluble Sub accumulation ofundissolved solid formed at the bottom of the stance remaining after performance of the Tyndall effect Disprinbeaker, but not in the beaker containing aspirin (L)- experiment was carried out. The dispersion in the beaker theanine cocrystal product which displayed a crystal-clear containing the dissolved aspirin: (L)-theanine cocrystal prod Solution. uct was stirred to collect any undissolved solid in the center. 30 No undissolved solids were observed at the bottom of the Tyndall Experiment 2 beaker with the aspirin: (L)-theanine cocrystal product. Both water and the aspirin: (L)-theanine cocrystal product pro Comparison of Aspirin: (L)-Theanine Cocrystal duced crystal-clear Solutions and were indistinguishable from Product with Aspro Clear one other. 35 300 mg of the aspirin: (L)-theanine cocrystal product was Tyndall Effect Experiment 5 dissolved in 150 ml of water in one beaker and a 300 mg tablet of Aspro Clear was dispersed in 150 ml water in another Comparison of Aspirin: (D)-Theanine Cocrystal beaker. A 514 nm laser beam was first passed through the Product with Dispirin aspirin: (L)-theanine cocrystal solution and then through the 40 Aspro Clear dispersion. A strong Tyndall effect was observed 300 mg of the aspirin: (D)-theanine cocrystal product was in the aqueous dispersion of Aspro Clear, but was not dissolved in 150 ml of water in one beaker and a 325 mg tablet observed with the composition according to the present of Disprin was dispersed in 150 ml of water in another beaker. invention dissolved in water. A 514 nm laser beam was first passed through the aspirin: An investigation regarding the degree of insoluble Sub 45 (D)-theanine cocrystal solution and then through the Disprin stance remaining after performance of the Tyndall effect dispersion. A strong Tyndall effect was observed in the aque experiment was carried out. The dispersions in the beakers ous dispersion of Disprin, but was not observed with the were stirred to collect any undissolved solid in the center. An composition according to the present invention dissolved in accumulation ofundissolved solid formed at the bottom of the Water. Aspro Clear beaker, but not in the beaker containing aspirin: 50 An investigation regarding the degree of insoluble Sub (L)-theanine cocrystal product which exhibited a crystal stance remaining after performance of the Tyndall effect clear Solution. experiment was carried out. The dispersions in the beakers were stirred to collect any undissolved solid in the center. An Tyndall Effect Experiment 3 accumulation ofundissolved solid formed at the bottom of the 55 Disprin beaker, but not in the beaker containing aspirin (D)- Comparison of Aspirin: (L)-Theanine Cocrystal theanine cocrystal product which displayed a crystal-clear Product with Bayer Aspirin Solution. 300 mg of the aspirin: (L)-theanine cocrystal product was Tyndall Effect Experiment 6 dissolved in 150 ml of water in one beaker and a 325 mg tablet 60 of Bayer aspirin was dispersed in 150 ml of water in another Comparison of Aspirin: (D)-Theanine Cocrystal beaker. A 514 nm laser beam was first passed through the Product with Aspro Clear aspirin: (L)-theanine cocrystal solution and then through the Bayer aspirin dispersion. A strong Tyndall effect was 300 mg of the aspirin: (D)-theanine cocrystal product was observed in the aqueous dispersion of Bayer aspirin, but was 65 dissolved in 150 ml of water in one beaker and a 300 mg tablet not observed with the composition according to the present of Aspro Clear was dispersed in 150 ml water in another invention dissolved in water. beaker. A 514 nm laser beam was first passed through the US 9,289,438 B2 15 16 aspirin: (D)-theanine cocrystal Solution and then through the of Disprin was dispersed in 150 ml of water in another beaker. Aspro Clear dispersion. A strong Tyndall effect was observed A 514 nm laser beam was first passed through the aspirin: in the aqueous dispersion of Aspro Clear, but was not (DL)-theanine cocrystal solution and then through the Dis observed with the composition according to the present prin dispersion. A strong Tyndall effect was observed in the invention dissolved in water. 5 aqueous dispersion of Disprin, but was not observed with the An investigation regarding the degree of insoluble Sub composition according to the present invention dissolved in stance remaining after performance of the Tyndall effect Water. experiment was carried out. The dispersions in the beakers An investigation regarding the degree of insoluble Sub were stirred to collect any undissolved solid in the center. An stance remaining after performance of the Tyndall effect accumulation ofundissolved solid formed at the bottom of the experiment was carried out. The dispersions in the beakers Aspro Clear beaker, but not in the beaker containing aspirin: 10 were stirred to collect any undissolved solid in the center. An (D)-theanine cocrystal product which displayed a crystal accumulation ofundissolved solid formed at the bottom of the clear Solution. Disprinbeaker, but not in the beaker containing aspirin: (DL)- theanine cocrystal product which displayed a crystal-clear Tyndall Effect Experiment 7 Solution. 15 Comparison of Aspirin: (D)-Theanine Cocrystal Tyndall Effect Experiment 10 Product with Bayer Aspirin Comparison of Aspirin: (DL)-Theanine Cocrystal 300 mg of the aspirin: (D)-theanine cocrystal product was Product with Aspro Clear dissolved in 150 ml of water in one beaker and a 325 mg tablet 20 of Bayer aspirin was dispersed in 150 ml of water in another 300 mg of the aspirin: (DL)-theanine cocrystal product was beaker. A 514 nm laser beam was first passed through the dissolved in 150 ml of water in one beaker and a 300 mg tablet aspirin: (D)-theanine cocrystal Solution and then through the of Aspro Clear was dispersed in 150 ml water in another Bayer aspirin dispersion. A strong Tyndall effect was beaker. A 514 nm laser beam was first passed through the observed in the aqueous dispersion of Bayer aspirin, but was as aspirin: (DL)-theanine cocrystal solution and then through not observed with the composition according to the present the Aspro Clear dispersion. A strong Tyndall effect was invention dissolved in water. observed in the aqueous dispersion of Aspro Clear, but was An investigation regarding the degree of insoluble Sub not observed with the composition according to the present stance remaining after performance of the Tyndall effect invention dissolved in water. experiment was carried out. The dispersions in the beakers An investigation regarding the degree of insoluble Sub were stirred to collect any undissolved solid in the center. An 30 stance remaining after performance of the Tyndall effect accumulation ofundissolved solid formed at the bottom of the experiment was carried out. The dispersions in the beakers Bayer aspirin beaker, but not in the beaker containing aspirin were stirred to collect any undissolved solid in the center. An (D)-theanine cocrystal product which displayed a crystal accumulation ofundissolved solid formed at the bottom of the clear Solution. Aspro Clear beaker, but not in the beaker containing aspirin 35 (DL)-theanine cocrystal product which displayed a crystal Tyndall Effect Experiment 8 clear Solution. Comparison of Aspirin: (D)-Theanine Cocrystal Tyndall Effect Experiment 11 Product with Water 40 Comparison of Aspirin: (DL)-Theanine Cocrystal 300 mg of the aspirin: (D)-theanine cocrystal product was Product with Bayer Aspirin dissolved in 150 ml of water in one beaker and 150 ml of water alone was placed in another beaker. A 514 nm laser beam was first passed through the aspirin: (D)-theanine coc 300 mg of the aspirin: (DL)-theanine cocrystal product was rystal Solution and then through the water. A strong Tyndall dissolved in 150 ml of water in one beaker and a 325 mg tablet effect was not observed with water, nor was it observed with 45 of Bayer aspirin was dispersed in 150 ml of water in another the composition according to the present invention dissolved beaker. A 514 nm laser beam was first passed through the in water. Both water and the aspirin: (D)-theanine cocrystal aspirin: (DL)-theanine cocrystal solution and then through product produced crystal-clear Solutions and were indistin the Bayer aspirin dispersion. A strong Tyndall effect was guishable from one other. observed in the aqueous dispersion of Bayer aspirin, but was An investigation regarding the degree of insoluble Sub 50 not observed with the composition according to the present stance remaining after performance of the Tyndall effect invention dissolved in water. experiment was carried out. The dispersion in the beaker An investigation regarding the degree of insoluble Sub containing the dissolved aspirin: (D)-theanine cocrystal prod stance remaining after performance of the Tyndall effect uct was stirred to collect any undissolved solid in the center. experiment was carried out. The dispersions in the beakers No undissolved solids were observed at the bottom of the 55 were stirred to collect any undissolved solid in the center. An beaker with the aspirin: (D)-theanine cocrystal product. Both accumulation ofundissolved solid formed at the bottom of the water and the aspirin: (D)theanine cocrystal product pro Bayer aspirin beaker, but not in the beaker containing aspirin duced crystal-clear Solutions and were indistinguishable from (DL)-theanine cocrystal product which displayed a crystal one other. clear Solution. 60 Tyndall Effect Experiment 9 Tyndall Effect Experiment 12 Comparison of Aspirin: (DL)-Theanine Cocrystal Comparison of Aspirin: (DL)-Theanine Cocrystal Product with Dispirin Product with Water 65 300 mg of the aspirin: (DL)-theanine cocrystal product was 300 mg of the aspirin: (DL)-theanine cocrystal product was dissolved in 150 ml of water in one beaker and a 325 mg tablet dissolved in 150 ml of water in one beaker and 150 ml of US 9,289,438 B2 17 18 water alone was placed in another beaker. A 514 nm laser ischemia, rheumatoid arthritis, osteoarthritis, inflammatory beam was first passed through the aspirin: (DL)-theanine bowel disease, and certain types of cancers. cocrystal Solution and then through the water. A strong Tyn Embodiments of the present invention have other potential dall effect was not observed with water, nor was it observed clinical applications including, but not limited to the follow with the composition according to the present invention dis 5 ing: cardiovascular (treatment of acute coronary syndrome, solved in water. Both water and the aspirin: (DL)-theanine treatment of acute myocardial infarction, adjunctive therapy cocrystal product produced crystal-clear Solutions and were in revascularization procedures: percutaneous transluminal indistinguishable from one other. coronary angioplasty, coronary artery bypass grafts, carotid An investigation regarding the degree of insoluble Sub enarterectomy, and stent implantation); neurologic (treat 10 ment of acute ischemic stroke); dysphagia (from any etiol stance remaining after performance of the Tyndall effect ogy); rheumatologic (rheumatoid arthritis, ankylosing experiment was carried out. The dispersion in the beaker spondylitis, spondyloarthropathies, pleurisy and arthritis of containing the dissolved aspirin: (DL)-theanine cocrystal systemic lupus erythematous, psoriatic arthritis, fibromyal product was stirred to collect any undissolved solid in the gia, Reiter's syndrome, osteoarthritis, Lyme arthritis and center. No undissolved solids were observed at the bottom of 15 gonorrhea arthritis); anti-inflammatory (epididymitis, Born the beaker with the aspirin: (DL)-theanine cocrystal product. holm's disease (coxsackie myocarditis), acute pericarditis, Both water and the aspirin: (DL)-theanine cocrystal product Dressler's syndrome, acute rheumatic fever, Ross River produced crystal-clear Solutions and were indistinguishable fever); pain management (marine envenomations such as from one other. from jellyfish, sea urchins, starfish, Portuguese man-of-wars, Derivatives prepared using compositions according to fire corals, sea anemones, lionfish, Stonefish, and stingrays; embodiments of the present invention can be administered via Osgood-Schlatter disease, idiopathic (primary) erythromela intravenous, intramuscular, intradermal. Subcutaneous, intra lgia, burns, acute renal colic, trigeminal neuralgia, bone pain peritoneal, intraarticular, Sublingual. Subconjunctival, and (osteoid osteomas, Pagets disease, sickle cell anemia), spinal intravitreal routes, or in the form of eye drops, orally, topi Stenosis, metastatic disease, intractable headaches, radiculo cally, rectally, via nasal spray, inhalation, and nanoparticle 25 pathies, and other chronic pain syndromes; as an adjuvant to delivery systems. morphine for patient-controlled analgesia (PCA); ophthal The pharmaceutical compositions according to embodi mologic (retinal ischemia and retinal occlusion); emergent ments of the present invention may be prepared as oral Solids use (in ambulances, hospital emergency rooms and critical (tablets, oral disintegrating tablets, effervescent tablets, cap care units, doctors offices, air travel, in the wilderness, etc.); Sules), oral liquids, hard or soft gelatin capsules, quick dis 30 with intubated patients and patients with severely compro Solve, controlled released, modified released, syrups, Suspen mised bowel function, excluding Crohn's disease and ulcer sions, granules, wafers (films), pellets, lozenges, powders, ative colitis; as an anti-pyretic for high grade temperatures, chewables, Suppositories, ointments, solutions, parenteral/ excluding malignant hyperthermia; for prevention of post injectable powders or granules that are pre-mixed or recon anesthetic shivering; for closure of patent ductus arteriosus; stituted, lotions, gels, creams, foams, and nanoemulsions. 35 for familial cylindromatosis; for inhibition of angiogenesis; The pharmaceutical compositions according to embodi for inhibition of niacin flushing; as an adjuvant to throm ments of the present invention may be combined with bolytic therapy for the treatment of frostbite; the treatment of lipooxygenase inhibitoragents, natural lipooxygenase inhibi rare diseases (including Kawasaki disease, Riedel thyroiditis, tors, anti-hypertensive agents, anti-hyperlipidemic agents, adult-onset Still's disease, Kikuchi-Fujimoto disease, focal anti-hypertensive/anti-hyperlipidemic agents, anti-triglycer 40 myositis, Weber-Christian disease, and adhesive arachnoidi ide agents, anti-migraine agents, blood modifier agents, espe tis); Substantial protection against hepatotoxic effects from cially thrombolytic agents and platelet aggregation inhibitor drugs, alcohol, herbs, toxins, chemicals, obesity-related liver agents, anti-neoplastic agents, anti-psychotic agents, anti disease and radiation-induced liver disease; and for providing anxiety agents, anti-convulsant agents, anti-Parkinsonian anti-HIV effects. agents, anti-diabetic agents, anti-inflammatory agents such as 45 Embodiments of the present invention may be employed to corticosteroids, anti-pyretic agents excluding NSAIDS provide Substantial protection against a wide variety of medi (NSAIDS when combined with aspirin, negate the effects of cal conditions, including but not limited to, the hepatotoxic aspirin), anti-rheumatic agents excluding NSAIDS, agents effects from Tylenol, statins, antiretrovirals, alcohol, and for treatment of symptoms associated with premenstrual Syn other drugs, toxins, herbs, and chemicals that are capable of drome excluding NSAIDS, anti-arrhythmic agents, digitalis 50 inducing hepatoxicity: obesity-related liver disease; and glycosides, anti-anginal agents (nitrates, anti-platelet agents, radiation-induced liver disease. beta blockers, calcium channel blockers and ranolazine), Cocrystals according to embodiments of the present inven analgesic agents, musculoskeletal relaxants, anti-infective tion may be used to improve one or more physical properties, agents especially antibiotics, parenteral nutritional agents, such as solubility, stability, and dissolution rate, of the active magnesium, Co-enzyme Quo, Sarcosine, amino acids, Vita 55 pharmaceutical ingredient of a selected treatment or preven mins (except vitamin K), and agents used to treat diseases tion. associated with excess amounts of glutamate Such as, but not While specific embodiments of the invention have been limited to amyotrophic lateral Sclerosis, cerebrovascular shown and described in detail to illustrate the application of dementia, and with brain injuries, as occurs with non-hemor the principles of the invention, it will be understood that the rhagic strokes or physical injuries. The pharmaceutical com 60 invention may be embodied otherwise without departing positions of the invention with theanine are not limited to from Such principles. these agents. Intravenous formulations according to embodiments of the What is claimed is: present invention include new compounds that are combined 1. A method of treating high grade temperature in a subject lipooxygenase/cyclooxygenase inhibitors for treatment of 65 in need thereof by administering to the subject an effective among other things, myocardial ischemia, myocardial infarc amount of a water-soluble composition comprising: a cocrys tion, cerebral ischemia, stroke, atherosclerosis, retinal tal composition containing a quantity of acetylsalicylic acid US 9,289,438 B2 19 20 and a quantity of a theanine enantiomer selected from the drying said solution for a length of time sufficient to pro group consisting of L-theanine, D-theanine, and DL-thean duce a dried crystalline mass of an aspirin-theanine coc 10. rystal composition. 2. The method of claim 1, wherein said quantity of acetyl 12. The method of claim 11, wherein said treatment is salicylic acid comprises about 50% by weight of said mixture. 5 achieved by an administration means selected from the group 3. The method of claim 1, wherein said mixture has an consisting of intravenous route, intramuscular route, intrad aqueous solubility of at least about 9.0 mg/mL. ermal route, subcutaneous route, intraperitoneal route, 4. The method of claim 1, wherein said mixture has an intraarticular route, Sublingual route, subconjunctival route, aqueous solubility of at least about 9.4 mg/mL. and intravitreal route. 5. The method of claim 1, wherein said mixture further 10 comprises a Sugar alcohol. 13. A method of treating high grade temperature in a sub 6. The method of claim 5, wherein said sugar alcohol has an ject in need thereof by administering to the subject an effec L-configuration. tive amount of a water-soluble aspirin-theanine cocrystal 7. The method of claim 1, wherein said water soluble composition, the composition made by a method comprising composition is combined with an agent for treatment of high 15 the steps of: grade temperature prior to administration. providing a quantity of acetylsalicylic acid; 8. The method of claim 1, wherein said treatment is adding a quantity of a theanine enantiomer selected from achieved by an administration means selected from the group the group consisting of L-theanine, D-theanine, and DL consisting of intravenous route, intramuscular route, intrad theanine to said quantity of acetylsalicylic acid to form a ermal route, subcutaneous route, intraperitoneal route, mixture comprising said quantity of acetylsalicylic acid intraarticular route, Sublingual route. Subconjunctival route, and said enantiomer of theanine; and intravitreal route. wetting said mixture; and 9. A method of treating high grade temperature in a subject grinding said mixture for a length of time sufficient to in need thereof by administering to the subject an effective produce a dried crystalline mass. amount of a water-soluble composition comprising a cocrys 25 14. The method of claim 13, wherein said treatment is tal composition containing a quantity of acetylsalicylic acid achieved by an administration means selected from the group and a quantity of L-Theanine, the composition made by a consisting of intravenous route, intramuscular route, intrad process comprising the steps of: ermal route, subcutaneous route, intraperitoneal route. providing a quantity of acetylsalicylic acid; intraarticular route, Sublingual route, subconjunctival route. and intravitreal route. adding a quantity of L-Theanine to said quantity of acetyl 30 Salicylic acid to form a mixture comprising said quantity 15. A method of treating high grade temperature in a sub of acetylsalicylic acid and said L-Theanine: ject in need thereof by administering to the subject an effec wetting said mixture; and grinding said mixture for a tive amount of a water-soluble aspirin-theanine cocrystal length of time sufficient to produce a dried crystalline composition, the composition made by a method comprising aSS. 35 the steps of: 10. The method of claim 9, wherein said treatment is providing a quantity of acetylsalicylic acid; achieved by an administration means selected from the group adding a quantity of a theanine enantiomer selected from consisting of intravenous route, intramuscular route, intrad the group consisting of L-theanine, D-theanine, and DL ermal route, subcutaneous route, intraperitoneal route. theanine to said quantity of acetylsalicylic acid to form a intraarticular route, Sublingual route, subconjunctival route, 40 mixture comprising said quantity of acetylsalicylic acid and intravitreal route. and said quantity of a theanine enantiomer; 11. A method of treating high grade temperature in a sub dissolving said mixture in a quantity of a first solvent to ject in need thereof by administering to the subject an effec form a solution; and tive amount of a water-soluble composition comprising a drying said solution for a length of time sufficient to pro cocrystal composition containing a quantity of acetylsalicylic 45 duce a dried crystalline mass of an aspirin-theanine coc acid and a quantity of L-Theanine, the composition made by rystal composition. a process comprising the steps of: 16. The method of claim 15, wherein said treatment is providing a quantity of acetylsalicylic acid; achieved by an administration means selected from the group adding a quantity of L-Theanine to said quantity of acetyl consisting of intravenous route, intramuscular route, intrad Salicylic acid to form a mixture comprising said quantity 50 ermal route, subcutaneous route, intraperitoneal route. of acetylsalicylic acid and said quantity of L-Theanine: intraarticular route. Sublingual route, subconjunctival route. dissolving said mixture in a quantity of a first solvent to and intravitreal route. form a solution; and