Platform drug delivery system utilizing crystal engineering and theanine dissolution

Abstract

A platform drug delivery system and a method of improving the delivery of low solubility pharmaceuticals utilizing crystal engineering and Theanine dissolution resulting in enhanced bioactivity, dissolution rate, and solid state stability.

Claims

1. A cocrystal composition comprising L-theanine; and R-Ibuprofen, wherein the cocrystal is characterized by an X-ray powder diffraction pattern with peaks (2) at 13.10.2 degrees 2, 17.50.2 degrees 2, 21.90.2 degrees 2, and 26.30.2 degrees 2.

2. A method of treating soft tissue injury in a subject in need thereof, comprising administering to the subject an effective amount of a water-soluble composition comprising: a cocrystal containing R-Ibuprofen and L-theanine; wherein the cocrystal is characterized by an X-ray powder diffraction pattern with peaks (2) at 13.10.2 degrees 2, 17.50.2 degrees 2, 21.90.2 degrees 2, and 26.30.2 degrees 2.

3. A method of treating inflammatory pain in a subject in need thereof, comprising administering to the subject an effective amount of a water-soluble composition comprising: a cocrystal containing R-Ibuprofen and L-theanine; wherein the cocrystal is characterized by an X-ray powder diffraction pattern with peaks (2) at 13.10.2 degrees 2, 17.50.2 degrees 2, 21.90.2 degrees 2, and 26.30.2 degrees 2.

4. A method of treating acute renal colic pain, acute pericarditis pain, dental pain, or ligament injuries pain in a subject in need thereof, comprising administering to the subject an effective amount of a water-soluble composition comprising: a cocrystal containing R-Ibuprofen and L-theanine; wherein the cocrystal is characterized by an X-ray powder diffraction pattern with peaks (2) at 13.10.2 degrees 2, 17.50.2 degrees 2, 21.90.2 degrees 2, and 26.30.2 degrees 2.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) The following is a brief description of the drawings, which are presented for the purposes of illustrating the exemplary embodiments disclosed herein and not for the purposes of limiting the same.

(2) FIG. 1a is an x-ray powder diffraction pattern of the L-theanine/amoxicillin cocrystal;

(3) FIG. 1b is an infrared absorption spectrum of the L-theanine/amoxicillin cocrystal;

(4) FIG. 2a is an x-ray powder diffraction pattern of the L-theanine/ampicillin cocrystal;

(5) FIG. 2b is an infrared absorption spectrum of the L-theanine/ampicillin cocrystal;

(6) FIG. 3a is an x-ray powder diffraction pattern of the L-theanine/aripiprazole cocrystal;

(7) FIG. 3b is an infrared absorption spectrum of the L-theanine/aripiprazole cocrystal;

(8) FIG. 4a is an x-ray powder diffraction pattern of the L-theanine/bromocriptine cocrystal;

(9) FIG. 4b is an infrared absorption spectrum of the L-theanine/bromocriptine cocrystal;

(10) FIG. 5a is an x-ray powder diffraction pattern of the L-theanine/cabergoline cocrystal;

(11) FIG. 5b is an infrared absorption spectrum of the L-theanine/cabergoline cocrystal;

(12) FIG. 6a is an x-ray powder diffraction pattern of the L-theanine/cefadroxil cocrystal;

(13) FIG. 6b is an infrared absorption spectrum of the L-theanine/cefadroxil cocrystal;

(14) FIG. 7a is an x-ray powder diffraction pattern of the L-theanine/cefdinir cocrystal;

(15) FIG. 7b is an infrared absorption spectrum of the L-theanine/cefdinir cocrystal;

(16) FIG. 8a is an x-ray powder diffraction pattern of the L-theanine/dantrolene cocrystal;

(17) FIG. 8b is an infrared absorption spectrum of the L-theanine/dantrolene cocrystal;

(18) FIG. 9a is an x-ray powder diffraction pattern of the L-theanine/daptomycin cocrystal;

(19) FIG. 9b is an infrared absorption spectrum of the L-theanine/daptomycin cocrystal;

(20) FIG. 10a is an x-ray powder diffraction pattern of the L-theanine/diflunisal cocrystal;

(21) FIG. 10b is an infrared absorption spectrum of the L-theanine/diflunisal cocrystal;

(22) FIG. 11a is an x-ray powder diffraction pattern of the L-theanine/doxorubicin cocrystal;

(23) FIG. 11b is an infrared absorption spectrum of the L-theanine/doxorubicin cocrystal;

(24) FIG. 12a is an x-ray powder diffraction pattern of the L-theanine/efavirenz cocrystal;

(25) FIG. 12b is an infrared absorption spectrum of the L-theanine/efavirenz cocrystal;

(26) FIG. 13a is an x-ray powder diffraction pattern of the L-theanine/entacapone cocrystal;

(27) FIG. 13b is an infrared absorption spectrum of the L-theanine/entacapone cocrystal;

(28) FIG. 14a is an x-ray powder diffraction pattern of the L-theanine/epinephrine cocrystal;

(29) FIG. 14b is an infrared absorption spectrum of the L-theanine/epinephrine cocrystal;

(30) FIG. 15a is an x-ray powder diffraction pattern of the L-theanine/erythromycin cocrystal;

(31) FIG. 15b is an infrared absorption spectrum of the L-theanine/erythromycin cocrystal;

(32) FIG. 16a is an x-ray powder diffraction pattern of the L-theanine/febuxostat cocrystal;

(33) FIG. 16b is an infrared absorption spectrum of the L-theanine/febuxostat cocrystal;

(34) FIG. 17a is an x-ray powder diffraction pattern of the L-theanine/fexofenadine cocrystal;

(35) FIG. 17b is an infrared absorption spectrum of the L-theanine/fexofenadine cocrystal;

(36) FIG. 18a is an x-ray powder diffraction pattern of the L-theanine/fluconazole cocrystal;

(37) FIG. 18b is an infrared absorption spectrum of the L-theanine/fluconazole cocrystal;

(38) FIG. 19a is an x-ray powder diffraction pattern of the L-theanine/furosemide cocrystal;

(39) FIG. 19b is an infrared absorption spectrum of the L-theanine/furosemide cocrystal;

(40) FIG. 20a is an x-ray powder diffraction pattern of the L-theanine/hydrochlorothiazide cocrystal;

(41) FIG. 20b is an infrared absorption spectrum of the L-theanine/hydrochlorothiazide cocrystal;

(42) FIG. 21a is an x-ray powder diffraction pattern of the L-theanine/R-ibuprofen cocrystal;

(43) FIG. 21b is an infrared absorption spectrum of the L-theanine/R-ibuprofen cocrystal;

(44) FIG. 22a is an x-ray powder diffraction pattern of the L-theanine/irinotecan cocrystal;

(45) FIG. 22b is an infrared absorption spectrum of the L-theanine/irinotecan cocrystal;

(46) FIG. 23a is an x-ray powder diffraction pattern of the L-theanine/levodopa cocrystal;

(47) FIG. 23b is an infrared absorption spectrum of the L-theanine/levodopa cocrystal;

(48) FIG. 24a is an x-ray powder diffraction pattern of the L-theanine/memantine cocrystal;

(49) FIG. 24b is an infrared absorption spectrum of the L-theanine/memantine cocrystal;

(50) FIG. 25a is an x-ray powder diffraction pattern of the L-theanine/metronidazole cocrystal;

(51) FIG. 25b is an infrared absorption spectrum of the L-theanine/metronidazole cocrystal;

(52) FIG. 26a is an x-ray powder diffraction pattern of the L-theanine/nilotinib cocrystal;

(53) FIG. 26b is an infrared absorption spectrum of the L-theanine/nilotinib cocrystal;

(54) FIG. 27a is an x-ray powder diffraction pattern of the L-theanine/prednisone cocrystal;

(55) FIG. 27b is an infrared absorption spectrum of the L-theanine/prednisone cocrystal;

(56) FIG. 28a is an x-ray powder diffraction pattern of the L-theanine/sulfamethoxazole amoxicillin cocrystal;

(57) FIG. 28b is an infrared absorption spectrum of the L-theanine/sulfamethoxazole cocrystal;

(58) FIG. 29a is an x-ray powder diffraction pattern of the L-theanine/sumitriptan cocrystal;

(59) FIG. 29b is an infrared absorption spectrum of the L-theanine/sumitriptan cocrystal;

(60) FIG. 30a is an x-ray powder diffraction pattern of the L-theanine/valganciclovir cocrystal;

(61) FIG. 30b is an infrared absorption spectrum of the L-theanine/valganciclovir cocrystal;

(62) FIG. 31a is an x-ray powder diffraction pattern of the L-theanine/zafirlukast cocrystal;

(63) FIG. 31b is an infrared absorption spectrum of the L-theanine/zafirlukast cocrystal;

(64) FIG. 32a is an x-ray powder diffraction pattern of the L-theanine/zidovudine cocrystal;

(65) FIG. 32b is an infrared absorption spectrum of the L-theanine/zidovudine cocrystal;

(66) FIG. 33a is an x-ray powder diffraction pattern of the L-theanine/gluconate-zinc cocrystal;

(67) FIG. 33b is an infrared absorption spectrum of the L-theanine/gluconate-zinc cocrystal;

(68) FIG. 34a is an x-ray powder diffraction pattern of the L-theanine/acyclovir cocrystal; and

(69) FIG. 34b is an infrared absorption spectrum of the L-theanine/acyclovir cocrystal.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(70) Embodiments of the present invention employ Theanine (5-N-ethyl glutamine) a non-protein amino acid found naturally in green tea leaves.

(71) Embodiments of the present invention include cocrystallization of low-solubility medication groups with Theanine (5-N-ethyl-glutamine).

(72) Embodiments of the present invention include cocrystallization of the following medication groups with theanine (5-N-ethyl-glutamine): nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, non-purine selective xanthine oxidase inhibitors, leukotriene receptor antagonists, beta-adrenergic agonists/alpha-adrenergic agonists, antihypertensive agents, loop diuretics, thiazide diuretics, atypical antipsychotic/partial dopamine agonists, non-steroidal anti-inflammatory drugs, corticosteroids, antihistamines (ethanolamines, histamine H1 receptor antagonists), antineoplastic agents (protein tyrosine kinase inhibitors/antileukemic drugs, topoisomerase 1 inhibitors, anthracycline topoisomerase inhibitors), antibacterial agents/antibiotics (cephalosporins, aminopenicillins, macrolides, sulfonamides, nitroimidazole antibiotics, fluorinated bistriazole antibiotics, cyclic lipopeptide antibiotics), antiviral agents, antifungal agents, antiprotozoan agents, immediate dopamine precursor agent, catechol-o-methyltransferase inhibitors, ergoline dopamine agonists, ergot derivative/dopamine D.sub.2, D.sub.3, D.sub.4, 5-HT.sub.1A, 5-HT.sub.2A, 5-HT.sub.2B, 5-HT.sub.2C, .sub.2B receptor agonists, antiparkinsonian agents, direct-acting skeletal muscle relaxants (hydantoin derivatives), noncompetitive NMDA (N-methyl D-aspartate receptor) antagonists, zinc salts of gluconic acid, serotonin-1b and serotonin-1d receptor agonists/antimigraine agents, cytomegalovirus nucleoside analog DNA polymerase inhibitors and guanosine analogue antiviral agents.

(73) The present invention is directed to, among other things, crystallization and theanine dissolution of medications from the following drug classes: nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, non-purine selective xanthine oxidase inhibitors, leukotriene receptor antagonists, beta-adrenergic agonists/alpha-adrenergic agonists, antihypertensive agents, loop diuretics, thiazide diuretics, atypical antipsychotic/partial dopamine agonists, non-steroidal anti-inflammatory drugs, corticosteroids, antihistamines (ethanolamines, histamine H1 receptor antagonists), antineoplastic agents (protein tyrosine kinase inhibitors/antileukemic drugs, topoisomerase 1 inhibitors, anthracycline topoisomerase inhibitors), antibacterial agents/antibiotics (cephalosporins, aminopenicillins, macrolides, sulfonamides, nitroimidazole antibiotics, fluorinated bistriazole antibiotics, cyclic lipopeptide antibiotics), antiviral agents, antifungal agents, antiprotozoan agents, immediate dopamine precursor agent, catechol-o-methyltransferase inhibitors, ergoline dopamine agonists, ergot derivative/dopamine D.sub.2, D.sub.3, D.sub.4, 5-HT.sub.1A, 5-HT.sub.2A, 5-HT.sub.2B, 5-HT.sub.2C, .sub.2B receptor agonists, antiparkinsonian agents, direct-acting skeletal muscle relaxants (hydantoin derivatives), noncompetitive NMDA (N-methyl D-aspartate receptor) antagonists, zinc salts of gluconic acid, serotonin-1b and serotonin-1d receptor agonists/antimigraine agents, cytomegalovirus nucleoside analog DNA polymerase inhibitors and guanosine analogue antiviral agents.

(74) Further, the Theanine contained in compositions according to embodiments of the present invention may be of any of L-form, D-form, DL-form.

(75) According to embodiments of the present invention the L-, D-, DL-alpha amino acids of Theanine and their side-chain carbon homologues (nor, homo, and bishomologues) may have a functional R-group, where R1 may contain linear, cyclic, or branched alkyl groups and derivatives thereof; linear, cyclic, or branched alkenyl groups and derivatives thereof; and aromatic radicals and derivatives thereof. In embodiments of the present invention, the aromatic radicals may be aryl radicals.

(76) According to the embodiments of the present invention in addition to L-Theanine, other analogues include D-Theanine, racemic Theanine or D, L-Theanine and its congeners including beta and reverse beta amino acid forms, shortened or nor-Theanine (aspartic acid analogue), and the lengthened homo-Theanines and their isomers. Further, gamma alkylamido analogues extend a full range of molecular property for drug cocrystals.

(77) According to the embodiments of the present invention the single enantiomers (S and R) and racemic forms (S, R-mixture) of the beta amino acids of Theanine may have a functional R-group, where R1 may contain linear, cyclic, or branched alkyl groups and derivatives thereof; linear, cyclic, or branched alkenyl groups and derivatives thereof; and aromatic radicals and derivatives thereof. In embodiments of the present invention, the aromatic radicals may be aryl radicals.

(78) Embodiments of the present invention may include cocrystal compositions of drugs from the classes listed below and the enantiomers, L- and D-isomers, D, L-racemic mixture, S- and R-isomers, S, R-racemic mixtures, all rotamers, tautomers, salt forms, and hydrates of the alpha and beta amino acids of Theanine in which the N-substituted functional R1-group [C4 or gamma-CH2-C(O)NR1] may contain linear, cyclic, or branched alkyl groups and derivatives thereof; linear, cyclic or branched alkenyl groups and derivatives thereof; and aromatic radicals (which may be aryl radicals) and derivatives thereof making up all the analogue forms of Theanine: nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, non-purine selective xanthine oxidase inhibitors, leukotriene receptor antagonists, beta-adrenergic agonists/alpha-adrenergic agonists, antihypertensive agents, loop diuretics, thiazide diuretics, atypical antipsychotic/partial dopamine agonists, non-steroidal anti-inflammatory drugs, corticosteroids, antihistamines (ethanolamines, histamine H1 receptor antagonists), antineoplastic agents (protein tyrosine kinase inhibitors/antileukemic drugs, topoisomerase 1 inhibitors, anthracycline topoisomerase inhibitors), antibacterial agents/antibiotics (cephalosporins, aminopenicillins, macrolides, sulfonamides, nitroimidazole antibiotics, fluorinated bistriazole antibiotics, cyclic lipopeptide antibiotics), antiviral agents, antifungal agents, antiprotozoan agents, immediate dopamine precursor agent, catechol-o-methyltransferase inhibitors, ergoline dopamine agonists, ergot derivative/dopamine D.sub.2, D.sub.3, D.sub.4, 5-HT.sub.1A, 5-HT.sub.2A, 5-HT.sub.2B, 5-HT.sub.2C, .sub.2B receptor agonists, antiparkinsonian agents, direct-acting skeletal muscle relaxants (hydantoin derivatives), noncompetitive NMDA (N-methyl D-aspartate receptor) antagonists, zinc salts of gluconic acid, serotonin-1b and serotonin-1d receptor agonists/antimigraine agents, cytomegalovirus nucleoside analog DNA polymerase inhibitors and guanosine analogue antiviral agents.

(79) Embodiments of the present invention include cocrystal compositions with Theanine dissolution of sumtriptan in combination with an NSAID.

(80) Embodiments of the present invention include cocrystal compositions with Theanine dissolution of Levodopa in combination with Entacapone.

(81) Embodiments of the present invention include cocrystal compositions with theanine dissolution of zinc gluconate in combination with (R)-Ibuprofen.

(82) Derivatives prepared using compositions according to embodiments of the present invention can be administered via intravenous, intramuscular, intradermal, transdermal, subcutaneous, intraperitoneal, intraventricular, intrathecal, intraarticular, sublingual, subconjunctival, and intravitreal routes, or in the form of eye drops, orally, topically, transmucosal, rectally, via nasal spray, inhalation, nanoparticle delivery systems, protein and peptide drug delivery systems, beaded delivery systems, mucosal vaccine delivery, colloidal drug carrier systems, controlled-released technology, liposomal and targeted drug delivery systems, iontophoretic devices to administer drugs through skin, programmable implanted drug-delivery devices, molecular targeting with immunoliposomes and other ligand-directed constructs, drug carriers featuring direct molecular targeting of cancer cells via antibody-mediated or other ligand-medicated interactions (Tiwari, G., Drug Delivery Systems: An updated review. Int J Pharm Ivestig. 2012 January-March; 2(1): 2-11).

(83) The pharmaceutical compositions according to embodiments of the present invention may be prepared as oral solids (tablets, oral disintegrating tablets, effervescent tablets, capsules), oral liquids, hard or soft gelatin capsules, microgels, microspheres, microcapsules, quick dissolve, controlled released, modified released, extended release, slow release, sustained release, syrups, suspensions, granules, wafer (films), pellets, lozenges, powders, chewable, suppositories, ointments, solutions, parenteral/injectable powders or granules that are pre-mixed or reconstituted, lotions, gels, creams, foams, propellants, strips, liposomes, proliposomes, prodrugs, cyclodextrins, m16 nasal and buccal aerosol sprays, encapsulated cells, oral soft gels, micellar solutions, vesicle and liquid crystal dispersions and nanoparticle dispersions (coated nanoparticles, pegylated nanoparticles, solid lipid particles, nanogels), and nanoemulsions (Tiwari, G., Drug Delivery Systems: An updated review. Int J Pharm Ivestig. 2012 January-March; 2(1): 2-11).

(84) Cocrystals according to embodiments of the present invention may be used to improve one or more physical properties, such as solubility, stability, and dissolution rate, of the active pharmaceutical ingredient of a selected treatment or prevention.

(85) Next, the present invention will be described in further detail by means of examples, without intending to limit the scope of the present invention to these examples alone. The following are exemplary formulations with cocrystal compositions and Theanine dissolution from the following medication groups in accordance with the present invention: nucleoside analog reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, non-purine selective xanthine oxidase inhibitors, leukotriene receptor antagonists, beta-adrenergic agonists/alpha-adrenergic agonists, antihypertensive agents, loop diuretics, thiazide diuretics, atypical antipsychotic/partial dopamine agonists, non-steroidal anti-inflammatory drugs, corticosteroids, antihistamines (ethanolamines, histamine H1 receptor antagonists), antineoplastic agents (protein tyrosine kinase inhibitors/antileukemic drugs, topoisomerase 1 inhibitors, anthracycline topoisomerase inhibitors), antibacterial agents/antibiotics (cephalosporins, aminopenicillins, macrolides, sulfonamides, nitroimidazole antibiotics, fluorinated bistriazole antibiotics, cyclic lipopeptide antibiotics), antiviral agents, antifungal agents, antiprotozoan agents, immediate dopamine precursor agent, catechol-o-methyltransferase inhibitors, ergoline dopamine agonists, ergot derivative/dopamine D.sub.2, D.sub.3, D.sub.4, 5-HT.sub.1A, 5-HT.sub.2A, 5-HT.sub.2B, 5-HT.sub.2C, .sub.2B receptor agonists, antiparkinsonian agents, direct-acting skeletal muscle relaxants (hydantoin derivatives), noncompetitive NMDA (N-methyl D-aspartate receptor) antagonists, zinc salts of gluconic acid, serotonin-1b and serotonin-1d receptor agonists/antimigraine agents, cytomegalovirus nucleoside analog DNA polymerase inhibitors and guanosine analogue antiviral agents.

(86) Experimental Details

(87) X-ray powder diffraction (XRPD) patterns were obtained using a Rigaku MiniFlex powder diffraction system, equipped with a horizontal goniometer operating in the /2 mode. The X-ray source was nickel-filtered K emission of copper (1.54184 ). Samples were packed into the sample holder using a back-fill procedure, and were scanned over the range of 3.5 to 40 degrees 2 at a scan rate of 0.5 degrees 2/min. Using a data acquisition rate of 1 point per second, these scanning parameters equate to a step size of 0.0084 degrees 2. Calibration of the diffractometer system was effected using purified talc as a reference material. The intensity scale for all diffraction patterns was normalized so that the relative intensity of the most intense peak in the pattern equaled 100%.

(88) Measurements of differential scanning calorimetry (DSC) were obtained on a TA Instruments 2910 thermal analysis system. Samples of approximately 1-2 mg were accurately weighed into an aluminum DSC pan, and then covered with an aluminum lid that was inverted and pressed down so as to tightly contain the powder between the top and bottom aluminum faces of the lid and pan. The samples were then heated over the temperature range of 20-250 C., at a heating rate of 10 C./min.

(89) Fourier-transform infrared absorption (FTIR) spectra were obtained at a resolution of 4 cm.sup.1 using a Shimadzu model 8400S spectrometer, with each spectrum being obtained as the average of 40 individual spectra. The data were acquired using the attenuated total reflectance (ATR) sampling mode, where the samples were clamped against the ZnSe/diamond crystal of a Pike MIRacle single reflection horizontal ATR sampling accessory. The intensity scale for all spectra was normalized so that the relative intensity of the most intense peak in the spectrum 100%.

EXAMPLE 1

(90) 0.327 g of amoxicillin trihydrate (0.780 mmol) and 0.136 g of L-theanine (0.781 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 1a, while the FTIR spectrum is shown in FIG. 1b. The DSC melting endotherm of the product was characterized by a peak maximum at 208 C.

EXAMPLE 2

(91) 0.311 g of ampicillin trihydrate (0.771 mmol) and 0.141 g of L-theanine (0.809 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 2a, while the FTIR spectrum is shown in FIG. 2b. The DSC melting endotherm of the product was characterized by a peak maximum at 212 C.

EXAMPLE 3

(92) 0.315 g of aripiprazole (0.703 mmol) and 0.129 g of L-theanine (0.741 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 3a, while the FTIR spectrum is shown in FIG. 3b. The DSC melting endotherm of the product was characterized by a peak maximum at 148 C.

EXAMPLE 4

(93) 0.165 g of bromocriptine (0.252 mmol) and 0.046 g of L-theanine (0.264 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 4a, while the FTIR spectrum is shown in FIG. 4b. The DSC melting endotherm of the product was characterized by a peak maximum at 197 C.

EXAMPLE 5

(94) 0.218 g of cabergoline (0.483 mmol) and 0.088 g of L-theanine (0.505 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 5a, while the FTIR spectrum is shown in FIG. 5b. The DSC melting endotherm of the product was characterized by a peak maximum at 52 C.

EXAMPLE 6

(95) 0.314 of cefadroxil monohydrate (0.849 mmol) and 0.151 g of L-theanine (0.867 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 6a, while the FTIR spectrum is shown in FIG. 6b. The DSC melting endotherm of the product was characterized by a peak maximum at 213 C.

EXAMPLE 7

(96) 0.335 of cefdinir monohydrate (0.810 mmol) and 0.140 g of L-theanine (0.804 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 7a, while the FTIR spectrum is shown in FIG. 7b. The DSC melting endotherm of the product was characterized by a peak maximum at 157 C.

EXAMPLE 8

(97) 0.208 g of cabergoline (0.662 mmol) and 0.115 g of L-theanine (0.660 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 8a, while the FTIR spectrum is shown in FIG. 8b. The DSC melting endotherm of the product was characterized by a peak maximum at 209 C.

EXAMPLE 9

(98) 0.256 g of daptomycin (0.158 mmol) and 0.030 g of L-theanine (0.172 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 9a, while the FTIR spectrum is shown in FIG. 9b. The DSC melting endotherm of the product was characterized by a peak maximum at 213 C.

EXAMPLE 10

(99) 0.373 g of diflunisal (1.491 mmol) and 0.269 g of L-theanine (1.544 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 10a, while the FTIR spectrum is shown in FIG. 10b. The DSC melting endotherm of the product was characterized by a peak maximum at 172 C.

EXAMPLE 11

(100) 0.077 g of doxorubicin (0.142 mmol) and 0.027 g of L-theanine (0.155 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 11a, while the FTIR spectrum is shown in FIG. 11b. The DSC melting endotherm of the product was characterized by a peak maximum at 209 C.

EXAMPLE 12

(101) 0.315 g of efavirenz (0.998 mmol) and 0.177 g of L-theanine (1.016 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 12a, while the FTIR spectrum is shown in FIG. 12b. The DSC melting endotherm of the product was characterized by a peak maximum at 136 C. EXAMPLE 13

(102) 0.227 g of entacapone (0.744 mmol) and 0.132 g of L-theanine (0.758 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 13a, while the FTIR spectrum is shown in FIG. 13b. The DSC melting endotherm of the product was characterized by a peak maximum at 160 C.

EXAMPLE 14

(103) 0.316 g of epinephrine (1.725 mmol) and 0.305 g of L-theanine (1.751 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 14a, while the FTIR spectrum is shown in FIG. 14b. The DSC melting endotherm of the product was characterized by a peak maximum at 205 C.

EXAMPLE 15

(104) 0.417 g of erythromycin (0.568 mmol) and 0.101 g of L-theanine (0.580 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 15a, while the FTIR spectrum is shown in FIG. 15b. The DSC melting endotherm of the product was characterized by a peak maximum at 219 C.

EXAMPLE 16

(105) 0.326 g of febuxostat (1.030 mmol) and 0.180 g of L-theanine (1.033 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 16a, while the FTIR spectrum is shown in FIG. 16b. The DSC melting endotherm of the product was characterized by a peak maximum at 182 C.

EXAMPLE 17

(106) 0.330 g of fexofenadine (0.658 mmol) and 0.119 g of L-theanine (0.683 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 17a, while the FTIR spectrum is shown in FIG. 17b. The DSC melting endotherm of the product was characterized by a peak maximum at 206 C.

EXAMPLE 18

(107) 0.355 g of fluconazole (1.159 mmol) and 0.204 g of L-theanine (1.171 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 18a, while the FTIR spectrum is shown in FIG. 18b. The DSC melting endotherm of the product was characterized by a peak maximum at 102 C.

EXAMPLE 19

(108) 0.181 g of furosemide (0.547 mmol) and 0.094 g of L-theanine (0.540 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 19a, while the FTIR spectrum is shown in FIG. 19b. The DSC melting endotherm of the product was characterized by a peak maximum at 193 C.

EXAMPLE 20

(109) 0.408 g of hydrochlorothiazide (1.370 mmol) and 0.239 g of L-theanine (1.372 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 20a, while the FTIR spectrum is shown in FIG. 20b. The DSC melting endotherm of the product was characterized by a peak maximum at 204 C.

EXAMPLE 21

(110) 0.246 g of R-ibuprofen (1.193 mmol) and 0.213 g of L-theanine (1.223 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 21a, while the FTIR spectrum is shown in FIG. 21b. The DSC melting endotherm of the product was characterized by a peak maximum at 51 C.

EXAMPLE 22

(111) 0.309 g of irinotecan (0.527 mmol) and 0.094 g of L-theanine (0.540 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 22a, while the FTIR spectrum is shown in FIG. 22b. The DSC melting endotherm of the product was characterized by a peak maximum at 218 C.

EXAMPLE 23

(112) 0.215 g of levodopa (1.090 mmol) and 0.191 g of L-theanine (1.096 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 23a, while the FTIR spectrum is shown in FIG. 23b. The DSC melting endotherm of the product was characterized by a peak maximum at 211 C.

EXAMPLE 24

(113) 0.142 g of memantine (0.792 mmol) and 0.140 g of L-theanine (0.804 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 24a, while the FTIR spectrum is shown in FIG. 24b. The DSC melting endotherm of the product was characterized by a peak maximum at 207 C.

EXAMPLE 25

(114) 0.335 g of metronidazole (1.957 mmol) and 0.348 g of L-theanine (1.998 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 25a, while the FTIR spectrum is shown in FIG. 25b. The DSC melting endotherm of the product was characterized by a peak maximum at 160 C.

EXAMPLE 26

(115) 0.271 g of nilotinib (0.512 mmol) and 0.090 g of L-theanine (0.517 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 26a, while the FTIR spectrum is shown in FIG. 26b. The DSC melting endotherm of the product was characterized by a peak maximum at 211 C.

EXAMPLE 27

(116) 0.206 g of prednisone (0.575 mmol) and 0.103 g of L-theanine (0.591 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 27a, while the FTIR spectrum is shown in FIG. 27b. The DSC melting endotherm of the product was characterized by a peak maximum at 201 C.

EXAMPLE 28

(117) 0.368 g of sulfamethoxazole (1.453 mmol) and 0.259 g of L-theanine (1.487 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 28a, while the FTIR spectrum is shown in FIG. 28b. The DSC melting endotherm of the product was characterized by a peak maximum at 169 C.

EXAMPLE 29

(118) 0.425 g of sumitriptan (0.963 mmol) and 0.168 g of L-theanine (0.964 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 29a, while the FTIR spectrum is shown in FIG. 29b. The DSC melting endotherm of the product was characterized by a peak maximum at 173 C.

EXAMPLE 30

(119) 0.348 g of valganciclovir (0.982 mmol) and 0.174 g of L-theanine (0.999 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 30a, while the FTIR spectrum is shown in FIG. 30b. The DSC melting endotherm of the product was characterized by a peak maximum at 212 C.

EXAMPLE 31

(120) 0.397 g of zafirlukast (0.690 mmol) and 0.122 g of L-theanine (0.700 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 31a, while the FTIR spectrum is shown in FIG. 31b. The DSC melting endotherm of the product was characterized by a peak maximum at 211 C.

EXAMPLE 32

(121) 0.343 g of zidovudine (1.283 mmol) and 0.226 g of L-theanine (1.297 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 32a, while the FTIR spectrum is shown in FIG. 32b. The DSC melting endotherm of the product was characterized by a peak maximum at 122 C.

EXAMPLE 33

(122) 0.398 g of gluconate zinc (0.873 mmol) and 0.157 g of L-theanine (0.901 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 33a, while the FTIR spectrum is shown in FIG. 33b. The DSC melting endotherm of the product was characterized by a peak maximum at 164 C.

EXAMPLE 34

(123) 0.384 g of Acyclovir (1.705 mmol) and 0.298 g of L-theanine (1.711 mmol) were weighed directly into the bowl of an agate mortar, and wetted with 70% isopropanol to form a moderately thick slurry. The slurry was thoroughly ground at the time of mixing, and then periodically re-ground until the contents were dry. The XRPD pattern of the product is shown in FIG. 34a, while the FTIR spectrum is shown in FIG. 34b. The DSC melting endotherm of the product was characterized by a peak maximum at 119 C.

(124) Embodiments of the present invention include compositions of Theanine combined with the drugs listed in the table below. Embodiments of the present invention employing crystallization and Theanine dissolution of low solubility pharmaceuticals are highly-efficacious in the treatment of a variety of emergent conditions where improved drug delivery would benefit patients, including those presenting with, but not limited to, the conditions in the table below, with the drug(s) for treating the condition(s) listed next to the condition(s):

(125) TABLE-US-00001 Condition(s) Drug Acute pulmonary edema/congestive heart failure Lasix Acute myocardial infarction Aspirin Acute ischemic stroke Aspirin Acute allergic/anaphylactic reactions from medications, food, Epinephrine latex, insect bites/stings Cardiac arrest, acute exacerbation of asthma, ventricular Epinephrine fibrillation, airway obstruction Australian box jelly fish envenomations Zinc gluconate Neurologic emergencies including malignant hyperthermia, Dantrolene sodium ecstasy intoxication/3,4-methylenedioxymethamphetamine, serotonin syndrome, 2,4-dinitrophenol poisoning.

(126) Embodiments of the present invention include compositions of Theanine combined with the drugs listed in the table below. Embodiments of the present invention employing crystallization and Theanine dissolution of low solubility pharmaceuticals are highly-efficacious in the treatment of a variety of additional conditions where improved drug delivery would benefit patients, including those presenting with, but not limited to, the conditions in the table below, with the drug(s) for treating the condition(s) listed next to the condition(s):

(127) TABLE-US-00002 Condition(s) Drug(s) Diseases/conditions associated with excessive amounts of Theanine glutamate: Spinal cord injury, stroke, traumatic brain injury, multiple sclerosis, Alzheimer's disease, Parkinson's disease, alcoholism, alcohol withdrawal, over-rapid benzodiazepine withdrawal, Huntington's disease, hypoglycemia, damage to a newborns brain caused by interrupted oxygen supply during delivery, exposure to nerve gas, and chronic nerve damage in such conditions as glaucoma, amyotrophic lateral sclerosis, and HIV dementia Parkinson's disease Levodopa, Entacapone, Nilotinib Hyperprolactinemia including amenorrhea with or without Bromocriptine galactorrhea, infertility or hypogonadism; prolactin-secreting adenomas, acromegaly, idiopathic or postencephalitic Parkinson's disease Hyperprolactinemic disorders, either idiopathic or due to Cabergoline pituitary adenomas Imatinib resistant chronic myelogenous leukemia, Alzheimer's Nilotinib disease, Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis Diseases/conditions associated with: Excessive amounts of Memantine glutamate, including moderate to severe Alzheimer's disease Neurodegenerative diseases such as muscle spasticity Dantrolene sodium associated with multiple sclerosis, cerebral palsy, spinal cord injury and cerebrovascular accidents Acute renal colic (R)-Ibuprofen, IV Aspirin Acute pericarditis (R)-Ibuprofen, SL/IV aspirin Dental pain, ligament injuries, (R)-Ibuprofen, SL Aspirin HIV/AIDS Efavirenz, Zidovudine Clostridium difficile, trichomoniasis, bacterial infections of the Metronidazole vagina, acne rosacea, giardiasis, amoebiasis, abscess, surgical wound infections, helicobacter infections, pseudomembranous enterocolitis, bacteroides infections Cytomegalovirus retinitis in patients who have AIDS, AIDS Valganciclovir associated opportunistic infections, prevents CMV disease in patients who have received an organ transplant Herpes simplex encephalitis, herpes labialis (cold sores), Acyclovir genital herpes, varicella-zoster (shingles and chickenpox), acute mucocutaneous HSV infections in immunocompromised patients, acute chickenpox in immunocompromised patients, ophthalmic herpes and herpes simplex blepharitis Oral candida/fungal infections Fluconazole Listeriosis Ampicillin Bronchitis, diphtheria, Legionnaires disease, pertussis Erythromycin pneumonia, dental prophylaxis Uncomplicated urinary tract infections, pneumocystis carinii Sulfamethoxzole pneumonia, toxoplasmosis, shigellosis, traveler's diarrhea Community-acquired pneumonia, acute exacerbations of Cefdinir chronic bronchitis, acute maxillary sinusitis, pharyngitis, tonsillitis, uncomplicated skin and soft tissue infections, acute bacterial otitis media Impetigo/soft tissue infections Cefadroxil Pharyngitis, tonsillitis, uncomplicated skin and soft tissue Amoxicillin infections, lower respiratory infections, early stage Lyme disease Staphylococcus aureus bacteremia including right sided Daptomycin endocarditis, complicated skin and skin structure gram-positive bacterial infections including MRSA Gout/hyperuricemia Febuxostat Heart failure, hypertension, pulmonary edema, fluid retention Lasix (edema) associate with ascites, liver cirrhosis, nephrotic syndrome Hypertension, heart failure, diabetes insipidus, fluid retention Hydrochlorothiazide (edema) in patients with congestive heart failure, cirrhosis of the liver, nephrotic syndrome in patients taking steroids or estrogen Migraine, cluster headaches Sumatriptan, IV/SL Aspirin Ramsay Hunt Syndrome Acyclovir, Prednisone Inflammation, autoimmune diseases, Bell's palsy, Hashimoto's Prednisone, encephalopathy, skin diseases, mild to moderate allergies, asthma, COPD, chronic inflammatory demyelinating polyneuropathy (CIDP), rheumatic disorders, allergic reactions, ulcerative colitis, Crohn's disease, adrenocortical insufficiency, thyroiditis, laryngitis, sinusitis, mild to moderate urticaria (hives), recurrent pericarditis, multiple sclerosis, nephrotic syndrome, myasthenia gravis, poison oak exposure, acute lymphoblastic leukemia, Non-Hodgkin lymphomas, Hodgkin's lymphoma, multiple myeloma and other hormone-sensitive tumors in combination with other anticancer drugs, uveitis, and sarcoidosis. Rhinovirus colds, Australian box jelly fish stings Zinc gluconate Acute lymphoblastic leukemia, acute myelobastic leukemia, Doxorubicin Wilm's tumor, neuroblastoma, soft tissue and bone sarcomas, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma, and bronchogenic carcinoma (small cell histologic type), and adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer Metastatic carcinoma of the colon and rectum Irinotecan Parkinson's disease and dopamine-responsive dystonias Levodopa Schizophrenia, bipolar disorder, autism Aripiprazole Pain, inflammation Diflunisal, (R)-Ibuprofen Asthma Zafirulkast, Prednisone, Hay fever Fexofenadine Stabilization of bimembrane structures Zinc Gluconate (R)-Ibuprofen

(128) While a specific embodiment of the invention has 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.