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(12) Patent Application Publication (10) Pub. No.: US 2010/0222294 A1 Pele (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2010/0222294 A1 Pele (43) Pub US 2010O222294A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0222294 A1 Pele (43) Pub. Date: Sep. 2,9 2010 (54) FORMULATIONS OF ATP AND ANALOGS OF Publication Classification ATP (51) Int. Cl. A 6LX 3L/7076 (2006.01) (75) Inventor: Amir Pelleg, Haverford, PA (US) A6IP35/00 (2006.01) Correspondence Address: 39t. 87, C FSH & RICHARDSON P.C. (2006.01) P.O. BOX 1022 A6IP 9/00 308: MNNEAPOLIS. MN 55440-1022 US A6IP II/06 2006.O1 9 (US) A6IP II/08 (2006.01) (73) Assignee: DUSKA SCIENTIFIC CO., CI2N 5/02 (2006.01) Philadelphia, PA (US) AOIN I/02 (2006.01) (52) U.S. Cl. ................................ 514/47; 435/375; 435/2 (21) Appl. No.: 12/715,170 (57) ABSTRACT (22) Filed: Mar. 1, 2010 This disclosure provides solutions and compositions (e.g., O O pharmaceutical solutions and compositions) containing Related U.S. Application Data adenosine 5'-triphosphate (ATP) or an analog thereof. In (60) Provisional application No. 61/156.263, filed on Feb. addition, it features methods of making and using the solu 27, 2009. tions and compositions. Patent Application Publication Sep. 2, 2010 US 2010/0222294 A1 Figure , NH N O O. O. a'rn HO-P-O-PYo-E-40. O-P-O- o, 's-slNYN Ohi Oi O US 2010/0222294 A1 Sep. 2, 2010 FORMULATIONS OF ATP AND ANALOGS OF N-Tris(hydroxymethyl)methylglycine (Tricine); glycine; ATP Diglycine (Gly-Gly); N,N-Bis(2-hydroxyethyl)glycine (Bi cine); N-(2-Hydroxyethyl)piperazine-N'-(4-butanesulfonic acid) (HEPBS); N-Tris(hydroxymethyl)methyl-3-amino 0001. This application claims priority of U.S. Provisional propanesulfonic acid (TAPS); 2-Amino-2-methyl-1,3-pro Application No. 61/156.263, filed Feb. 27, 2009, the entire panediol (AMPD); N-tris(Hydroxymethyl)methyl-4-ami disclosure of which is incorporated herein by reference in its nobutanesulfonic acid (TABS); N-(1,1-Dimethyl-2- entirety. hydroxyethyl)-3-amino-2-hydroxypropanesulfonic acid (AMPSO); 2-(Cyclohexylamino)ethanesulfonic acid TECHNICAL FIELD (CHES); 3-(Cyclohexylamino)-2-hydroxy-1-propane 0002 This invention relates to compositions containing sulfonic acid (CAPSO); or B-Aminoisobutyl alcohol (AMP). adenosine 5'-triphosphate (ATP), or analogs thereof, and 0009. Any of the solutions can further contain a stabilizer. more particularly to pharmaceutical compositions containing The stabilizer can beachelating agent, e.g., ethylenediamine ATP or analogs thereof. tetraacetic acid (EDTA) or ethylene glycol tetraacetic acid (EGTA). The stabilizer can also be a Sugar alcohol (e.g., BACKGROUND Sorbitol, mannitol, adonitol, erythritol, Xylitol, lactitol, iso malt, maltitol, or a cyclitol), glycerol, methionine, or creati 0003. Many therapeutic, prophylactic, and diagnostic uses 1C. for ATP, or analogs thereof, have been developed. There is a 0010. The ATP analog in any of the solutions can be: need for stable liquid pharmaceutical formulations of ATP C.B-methylene-ATP (C.BmATP); B.Y-methylene-ATP and analogs thereof in which their pharmacological activity is (B.YmATP); 2-thio-ATP (2-SH-ATP); 2-methylthio-ATP maintained. (2-MeS-ATP); 2',3'-O-2,4,6,-trinitrophenyl-ATP (TNP ATP); 2',3'-O-(4-benzoyl)-ATP (BZATP): an N-alkyl-2 ATP: SUMMARY adenosine 5'-(BY-imido) triphosphate (AMP-PNP); ATP 0004. This disclosure is based on the findings of the inven MgCl; or oxidized ATP (oATP). The concentration of ATP, tors that an alkaline solution of ATP is stable for at least six or the analog thereof, in the solutions can be about 18.15 mM years. The disclosure features stable solutions and pharma or about 36.30 mM. The concentration of glycine can be ceutical compositions containing ATP, or an analog thereof, about 13.32 mM. The solution can be one that includes: 18.15 and methods of making and using Such solutions and phar mM ATP; and NaHPO. Any of the solutions can be formu maceutical compositions. lated for parenteral administration to a Subject, e.g., for 0005 More specifically, the disclosure provides a first administration to a subject by injection. Alternatively, the aqueous solution containing: an aqueous solvent; an adenos Solutions can be formulated for intravenous administration, ine 5-triphosphate (ATP) reagent; and glycine, the Solution for enteral (e.g., oral) administration, for topical administra having a pH of between about 8.7 and about 9.5. tion, or for transdermal administration to a subject. 0006 Another aspect of the disclosure is a second aqueous 0011. In another embodiment, the disclosure provides a Solution that contains: an aqueous solvent; and an ATP method of making an aqueous solution. The method includes: reagent, the solution having a pH of about 8.7 to about 9.5 and mixing together water, glycine, and an ATP reagent to create being formulated for administration to a subject or for con a mixture; and adjusting the pH of the mixture to between tacting a mammalian cell with the ATP reagent. about 8.7 to about 9.5 to create the solution. The method can 0007 Also featured by the disclosure is a third aqueous further involve mixing into the mixture a biocompatible Solution containing: an aqueous solvent; and ATP, the solu buffer and/or mixing into the mixture a stabilizer. The pH can tion having a pH of between about 8.7 and about 9.5. The be adjusted by adding a base, e.g., sodium hydroxide, to the solution is such that, at the end of a period of time at about 4 mixture. The method can also further include storing the C. to about 8° C., it contains an amount of ADP that is not solution at a temperature of between about 4°C. and about 8° more than about 5.0% (e.g., not more than about 4.0%, not C. for a period of time of up to six years. Where the ATP more than about 3.0%, or not more than about 2.5%) of the reagent is ATP at the end of the period of time, the solution amount of ATP in the solution, the period of time being up to can contain an amount of ADP that is not more than about six years after the solution was made. 5.0% of the amount of ATP in the solution. 0008. In the solutions of the disclosure the ATP reagent 0012 Another aspect of the disclosure is an in vitro can be ATP or a pharmaceutically acceptable salt thereof. It method of delivering an ATP reagent to a mammalian cell. can also be an ATP analog or a pharmaceutically acceptable The method includes incubating the cell with a medium that salt thereof. The second and third aqueous solutions can fur contains any of the above Solutions in vitro. The mammalian ther contain glycine. The pH of any of solutions of the dis cell can be, for example, a spermatozoon. closure can be between about 8.7 and about 9.4, e.g., about 0013 Also provided by the invention is an in vivo method 8.8 and about 9.3. Moreover, any of the solutions can further of contacting a mammalian cell in a mammalian Subject with contain a biocompatible buffer, e.g., a phosphate buffer Such an ATP reagent. The method includes administering a com as a phosphate buffer that contains NaHPO and/or KHPO. position containing or being any of the solutions disclosed The biocompatible buffer can also be a bicarbonate buffer, an herein to the Subject, e.g., a human Subject. The method can acetate buffer, a citrate buffer, or a glutamate buffer. In addi be a therapeutic method, a prophylactic method, or a diag tion, any of the Solutions can contain one or more of 1,3-Bis nostic method. In the method, the Subject can have, be sus tris(hydroxymethyl)methylaminopropane (Bis-Tris Pro pected of having, or be at risk of developing a condition pane); Tris(hydroxy)aminomethane (Tris); Tris selected from an obstructive pulmonary disease (OPD), (hydroxymethyl)aminomethane (Trizma); 4-(2- asthenozoospermia, pain, tissue injury, nerve damage, organ Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS): failure, a condition requiring reduction in blood pressure, US 2010/0222294 A1 Sep. 2, 2010 pulmonary hypertension, tachycardia, myocardial ischemia, materials are described below, although methods and materi coronary artery disease, cystic fibrosis, cancer, and cancer als similar or equivalent to those described herein can be used related cachexia. The cell can be a neuron (e.g., a retinal in the practice or testing of the present invention. All publi neuron, a cortical neuron, a hippocampal neuron, a basal cations, patent applications, patents and other references ganglion neuron, a spinal cord neuron, a pulmonary vagal C mentioned herein are incorporated by reference in their fiber, or a pulmonary vagal A fiber), a spermatozoon, a vas entirety. The materials, methods, and examples disclosed cular Smooth muscle cell, or a vascular endothelial cell. herein are illustrative only and not intended to be limiting. Moreover the cell can be a cancer cell or a normal cell. The 0021. Other features and advantages of the invention, e.g., OPD can be chronic obstructive pulmonary disease (COPD), stable ATP formulations, will be apparent from the following chronic asthma, acute bronchitis, emphysema, chronic bron description, from the drawings and from the claims. chitis, bronchiectasis, cystic fibrosis, cough, or acute asthma. The method can be a method to determine whether the subject DESCRIPTION OF DRAWINGS has COPD or asthma or a method for assessing the efficacy of a treatment for an OPD. Where the cell is a spermatozoon, the 0022 FIG. 1 is a depiction of the chemical structure of method can further involve testing the motility of the sper ATP. Greek lettering (C, B, and Y) shows the phosphorus matozoon.
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