Formulations of ATP and Analogs of ATP
This disclosure provides solutions and compositions (e.g., pharmaceutical solutions and compositions) containing adenosine 5′-triphosphate (ATP) or an analog thereof. In addition, it features methods of making and using the solutions and compositions.
1 . An aqueous solution comprising a mixture selected from the group consisting of:
(a) an aqueous solvent,
an adenosine 5-triphosphate (ATP) reagent, and
glycine,
wherein the solution has a pH of between about 8.7 and about 9.5;
(b) an aqueous solvent, and
an ATP reagent,
wherein the solution has a pH of about 8.7 to about 9.5 and wherein the solution is formulated for administration to a subject or for contacting a mammalian cell with the ATP or the analog thereof; and
(c) an aqueous solvent, and
ATP,
wherein the solution has a pH of between about 8.7 and about 9.5,
such that the solution, at the end of a period of time at about 4° C. to about 8° C., contains an amount of ADP that is not more than about 5.0% of the amount of ATP in the solution, the period of time being up to six years after the solution was made.
2 . The solution of claim 1 , wherein:
(i) not more than about 5% of the ATP is not more than about 4.0% of ATP that the solution contained when the solution was made;
(ii) not more than about 5% of the ATP is not more than about 3.0% of ATP that the solution contained when the solution was made; or
(iii) not more than about 5% of the ATP is not more than about 2.5% of ATP that the solution contained when the solution was made.
3 . The aqueous solution claim 1 , wherein the ATP reagent is: ATP or a pharmaceutically acceptable salt thereof; or an ATP analog or a pharmaceutically acceptable salt thereof.
4 . The solution of claim 1 , wherein (b) and (c) further comprise glycine.
5 . The solution of claim 1 , wherein the solution has a pH of between about 8.7 and about 9.4 or between about 8.8 and about 9.3.
6 . The solution of claim 1 , further comprising one or both of a biocompatible buffer and a stabilizer.
7 . The solution of claim 6 , wherein the biocompatible buffer is a phosphate buffer.
8 . The solution of claim 7 , wherein the phosphate buffer comprises Na 2 HPO 4 .
9 . The solution of claim 6 , wherein the biocompatible buffer is a bicarbonate buffer, an acetate buffer, a citrate buffer, or a glutamate buffer.
10 . The solution of claim 6 , wherein the solution comprises 2-(N-morpholino)ethanesulfonic acid (MES), tris(hydroxymethyl)aminomethane (Tris), (N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid] (HEPES), 3{[tris(hydroxymethyl)methyl]amino}propanesulfonic acid (TAPS), N,N-bis(2-hydroxymethyl)glycine (Bicine), N-tris(hydroxymethyl)methylglycine (Tricine), 2-{[tris(hydroxymethyl)methyl]amino}ethanesulfonic acid (TES), 3-(N-morpholino)propanesulfonic acid (MOPS), piperazine-N,N′-bis(2-ethanesulfonic acid) (PIPES), dimethylarsinic acid (Cacodylate), or 2-(N-morpholino)ethanesulfonic acid (MES).
11 . The solution of claim 6 , wherein the stabilizer is:
a chelating agent selected from the group consisting of ethylenediaminetetraacetic acid (EDTA) and ethylene glycol tetraacetic acid (EGTA);
a sugar alcohol selected from the group consisting of sorbitol, mannitol, adonitol, erythritol, xylitol, lactitol, isomalt, maltitol, or a cyclitol;
glycerol;
methionine; and
creatinine.
12 . The solution of claim 3 , wherein the ATP analog is selected from the group consisting of: α,β-methylene-ATP (α,βmATP); β,γ-methylene-ATP (β,γmATP); 2-thio-ATP (2-SH-ATP); 2-methylthio-ATP (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; adenosine 5′-(, -imido)triphosphate (AMP-PNP); ATP-MgCl2; and oxidized ATP (oATP).
13 . The solution of claim 1 , wherein concentration of the ATP reagent in the solution is: about 18.15 mM; about 36.30 mM; or about 13.32 mM.
14 . The solution of claim 1 , wherein the solution comprises:
18.15 mM ATP; and
Na 2 HPO 4 .
15 . The solution of claim 1 , wherein the solution is formulated for: parenteral administration to a subject; administration to a subject by inhalation; intravenous administration to a subject; enteral administration to a subject; oral administration to a subject; topical administration to a subject; or transdermal administration to a subject.
16 . A method of making an aqueous solution, the method comprising:
mixing together
water,
glycine,
and an ATP reagent to create a mixture; and
adjusting the pH of the mixture to between about 8.7 to about 9.5 to create the solution.
17 . The method of claim 16 , further comprising mixing into the mixture a biocompatible buffer.
18 . The method of claim 16 , further comprising mixing into the mixture a stabilizer.
19 . The method of claim 16 , further comprising storing the solution at a temperature of between about 4° C. and about 8° C. for a period of time of up to six years.
20 . The method of claim 19 , wherein the ATP reagent is ATP and the solution, at the end of the period of time, contains an amount of ADP that is not more than about 5.0% of the amount of ATP in the solution.
21 . An in vitro method of delivering an ATP reagent to a mammalian cell, the method comprising incubating the cell with a medium comprising the solution of claim 1 in vitro.
22 . The method of claim 21 , wherein the mammalian cell is spermatozoon.
23 . An in vivo method of contacting a mammalian cell in a mammalian subject with an ATP reagent, the method comprising administering a composition comprising the solution of claim 1 to the subject.
24 . The method of claim 23 , wherein the subject is a human subject.
25 . The method of claim 23 , wherein the method is a therapeutic method, a prophylactic method, or a diagnostic method.
26 . The method of claim 23 , wherein the subject has, is suspected of having, or is at risk of developing a condition selected from the group consisting of an obstructive pulmonary disease (OPD), asthenozoospermia, pain, tissue injury, nerve damage, organ failure, a condition requiring reduction in blood pressure, pulmonary hypertension, tachycardia, myocardial ischemia, coronary artery disease, cystic fibrosis, cancer, and cancer-related cachexia.
27 . The method of claim 23 , wherein the cell is a neuron, a spermatozoon, a vascular smooth muscle cell, a vascular endothelial cell, or a cancer cell.
28 . The method of claim 27 , wherein the neuron is retinal neuron, a cortical neuron, a hippocampal neuron, a basal ganglion neuron, a spinal cord neuron, a pulmonary vagal C fiber, or a pulmonary vagal A fiber.
29 . The method of claim 26 , wherein the OPD is selected from the group consisting of chronic obstructive pulmonary disease (COPD), chronic asthma, acute bronchitis, emphysema, chronic bronchitis, bronchiectasis, cystic fibrosis, cough, and acute asthma.
30 . The method of claim 23 , wherein the method is a method: (a) to determine whether the subject has COPD or asthma; (b) for assessing the efficacy of a treatment for an OPD.
31 . The method of claim 22 , further comprising testing the motility of the spermatozoon.
32 . A kit comprising:
(a) the solution of claim 1 and instructions for administering the solution to a subject; or
(b) an ATP reagent, glycine, and instructions for making the solution of claim 1 .
33 . The kit of claim 32 , wherein (b) further comprises Na 2 HPO4.