US 2014027.4936A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0274936A1 Piccariello et al. (43) Pub. Date: Sep. 18, 2014
(54) COORDINATION COMPLEXES, (60) Provisional application No. 60/621,747, filed on Oct. PHARMACEUTICAL SOLUTIONS 25, 2004. COMPRISING COORONATION COMPLEXES, AND METHODS OF Publication Classification TREATING PATIENTS (51) Int. Cl. C07H 17/02 (2006.01) (71) Applicant: SYNTHONICS, INC., BLACKSBURG, C07F 3/02 (2006.01) VA (US) C07F 15/04 (2006.01) (72) Inventors: Thomas Piccariello, Blacksburg, VA C07F 3/00 (2006.01) (US); John D. Price, Blacksburg, VA C7F 3/06 (2006.01) (US); Robert A. Oberlender, C07F 15/02 (2006.01) Blacksburg, VA (US); Michaela E. (52) U.S. Cl. Mulhare, Christiansburg, VA (US); CPC C07H 17/02 (2013.01); C07F 3/06 (2013.01); Mary C. Spencer, Blacksburg, VA (US); C07F 15/02 (2013.01); C07F 15/04 (2013.01); Scott B. Palmer, Wilmette, IL (US) C07F 3/00 (2013.01); C07F 3/02 (2013.01) USPC ...... 514/43; 549/212:549/310: 514/186: 514/470; 552/504: 552/588: 514/179; 544/226; (73) Assignee: SYNTHONICS, INC., BLACKSBURG, 544/225; 544/276; 514/263.2: 514/150; VA (US) 536/28.7 (21) Appl. No.: 14/290,877 (57) ABSTRACT A coordination complex having a physiologically acceptable (22) Filed: May 29, 2014 pK, includes a metal and a biologically active agent. The pK, of the coordination complex is less than the pKa of the bio logically active agent. A pharmaceutical Solution for treating Related U.S. Application Data a patient includes a coordination complex and water, wherein (63) Continuation of application No. 12/788,073, filed on the coordination complex is at least partially soluble in the May 26, 2010, now Pat. No. 8,779,175, which is a water at physiological pH and in a therapeutically efficacious continuation-in-part of application No. 1 1/824,411, concentration. A method for treating a patient includes filed on Jun. 29, 2007, now Pat. No. 7,799,937, which administering a pharmaceutical Solution including a coordi is a continuation-in-part of application No. 1 1/257, nation complex and water to a patient in need of a biologically 504, filed on Oct. 24, 2005, now abandoned. active agent. Patent Application Publication Sep. 18, 2014 Sheet 1 of 3 US 2014/0274936A1
FIG. 1
OH N
pKa = 9.2 log D74 = 1.46 oral bioavailability = 43% BCS Class = IV solubility = 0.1 mg/mL at 25°C
+1 Patent Application Publication Sep. 18, 2014 Sheet 2 of 3 US 2014/0274936A1
Arg NH NH Lys H NH His
H N O pH HO O HN N O N i\- 2-nO Y'oh5 > n-so 5- -o HO- OH 1YNH HO HO HO OH OH Carnosine HN-4 Tricine AscOrbic acid Quinic acid Patent Application Publication Sep. 18, 2014 Sheet 3 of 3 US 2014/0274936A1
YZ SAHA FG.5
IIIIIIIII||I||ITTITTI,IIIIIIIIIIIIIIIIIIII?d, IZIZIZ-Z-Z-Z-Z-Z- ?<<<<<<<<<<<<<<<|ZZZZZZZZZZZZZZZZ No. ITÍTETTI?IITTIIIIIIIIIIIITETT?T?T?TTTTTTTTTT-ÉR&<<<<<<< COORDINATION COMPLEXES, SUMMARY PHARMACEUTICAL SOLUTIONS COMPRISING COORDINATION 0007. The scope of the present invention is defined solely COMPLEXES, AND METHODS OF by the appended claims and is not affected to any degree by TREATING PATIENTS the statements within this Summary. 0008 A first coordination complex includes a metal and a biologically active agent. The coordination complex has a RELATED APPLICATIONS pK, that is less than a pKa of the biologically active agent and 0001. The present application is a continuation of U.S. the pKa of the coordination complex is physiologically patent application Ser. No. 12/788,073, filed May 26, 2010, acceptable, with a proviso that when the biologically active which is a continuation-in-part of prior U.S. patent applica agentis Suberoylanilide hydroxamic acid, the metal is neither tion Ser. No. 1 1/824,411, filed Jun. 29, 2007, and issued on iron nor zinc. Sep. 21, 2010, as U.S. Pat. No. 7,799,937, which is a continu 0009. A second coordination complex includes a metal ation-in-part of prior application Ser. No. 1 1/257,504, filed other than iron or Zinc and a biologically active agent. The Oct. 24, 2005, which claims the benefit of U.S. Provisional coordination complex has a pK, that is less than a pKa of the Application No. 60/621,747, filed Oct. 25, 2004. The entire biologically active agent, and the pKa of the coordination contents of all of these documents are incorporated herein by complex is physiologically acceptable. reference, except that in the event of any inconsistent disclo 0010. A third coordination complex includes a metal Sure or definition from the present specification, the disclo selected from the group consisting of magnesium, calcium, sure or definition herein shall be deemed to prevail. and nickel; and a biologically active agent. The coordination complex has a pK, that is less than a pKa of the biologically TECHNICAL FIELD active agent, and the pKa of the coordination complex is physiologically acceptable. 0002 The present teachings relate generally to metal coor 0011. A fourth coordination complex includes a metal dination complexes and methods for their therapeutic use in selected from the group consisting of magnesium, calcium, the treatment of patients. and nickel, and a biologically active agent selected from the group consisting of a Sulfamate, a hydroxamic acid, and a BACKGROUND dihydropyridine calcium channel blocker. The coordination complex has a pK that is less than a pKa of the biologically 0003. The therapeutic efficacy of pharmaceutical agents is active agent, and the pKa of the coordination complex is less oftentimes diminished as a result of their inadequate solubili than about 9. ties at physiological pH. In addition, the ability to administer 0012. A fifth coordination complex includes a metal and a Some pharmaceutical agents in aqueous solution—for biologically active agent, wherein water solubility of the example, via intraperitoneal (I.P.) injection, intramuscular coordination complex is greater than water solubility of the (I.M.) injection, intravenous (I.V.) injection, and the like—is biologically active agent at physiological pH, and wherein the oftentimes not practicable due to the inadequate solubilities pKa of the coordination complex is physiologically accept of the pharmaceutical agents at the requisite concentrations able. When the biologically active agent is suberoylanilide and/or pH. hydroxamic acid, then the metal is not a transition metal 0004 As a consequence of such inadequate solubilities, it unless the coordination complex further comprises a buffer is oftentimes necessary to restrict the formulation of pharma ing ligand. ceutical agents to peroral dosage forms. However, when oral 0013 A pharmaceutical solution for treating a patient administration is not feasible, practical or otherwise desirable includes a coordination complex of a type described herein (e.g., in the treatment of patients who are unable to Swallow— and water. The coordination complex is at least partially Such as neonates—as well as critically ill, paralyzed, and/or soluble in the water at physiological pH in a therapeutically comatose patients), the inability to administer the pharma efficacious concentration. ceutical agent in a parenteral dosage form is an acute prob 0014. A method for treating a patient includes administer lem. ing a pharmaceutical Solution of a type described herein to a 0005. A further limitation on the parenteral administration patient in need of the biologically active agent thereof. of pharmaceutical agents is observed in connection with com pounds having high pK values. Since pharmaceutical agents BRIEF DESCRIPTION OF THE DRAWINGS having high pK values typically form solutions with pH values that are above the level at which one could safely or 0015 FIG. 1 shows the molecular structure and biophar conveniently administer the drug, parenteral administration maceutical properties of Suberoylanilide hydroxamic acid of Such pharmaceutical agent is oftentimes not an option. (SAHA). Indeed, there are presently very few options available for 0016 FIG. 2 shows the enhancement of ligand polariza formulating solutions of pharmaceutical agents with high tion using topiramate (tpm) as a representative ligand. pK values. 0017 FIG. 3 shows a magnesium-coordinated topiramate 0006. In short, it would be highly desirable to (a) enhance Mg(tpm) and a magnesium-coordinated topiramate with a the aqueous solubilities of poorly soluble pharmaceutical histidine buffering ligand Mg(tpm) (his). agents in order to increase their utilities or availabilities at 0018 FIG. 4 shows molecular structures of representative physiological pH, and/or to (b) buffer the acidities of phar buffering ligands. maceutical agents to acceptable physiological levels without (0019 FIG. 5 shows a plot of data from breast cancer cell compromising their therapeutic efficacies. proliferation assays. US 2014/0274936 A1 Sep. 18, 2014 DETAILED DESCRIPTION 0026. By way of general introduction, a coordination complex in accordance with the present teachings includes a 0020. As further described below, the inventors have dis metal and a biologically active agent. The coordination com covered that coordinating a metal to a biologically active plex has a pK, that is physiologically acceptable and less than agent in a non-aqueous system favors the formation of a a pKa of the biologically active agent. coordination complex—as opposed to a salt and that the 0027. In some embodiments, the water solubility of the resultant coordination complex—unlike the corresponding coordination complex is greater than that of the biologically salt exhibits a Surprising and unexpected buffering effect. It active agent at physiological pH and/or is greater than that of has been discovered that as a result of this buffering effect, the a metal salt of the biologically active agent at physiological biologically active agent can remain soluble in water at physi pH. In some embodiments, the biologically active agent ological pH for a period of time sufficient for the preparation exhibits therapeutic efficacy against one or more diseases, of a safe and convenient parenteral (e.g., I.V.) formulation and at least a portion of the therapeutic efficacy is retained in and/or for delivering the biologically active agent to its target the coordination complex. It is to be understood that libera in the body. Thus, the coordination complexes described tion of the biologically active agent from the coordination herein resolve the above-described problems associated with complex may or may not be a prerequisite to releasing a drugs having poor water solubilities that heretofore could not safely be converted to injectable forms or that exhibited therapeutic efficacy of the drug (in other words, the free diminished bioavailabilities due to their inabilities to migrate biologically active agent and the coordination complex that to their target sites in the allotted time. The inventors have contains a metal-coordinated version of the biologically further discovered, Surprisingly and unexpectedly, that the active agent may each exhibit its own therapeutic efficacy). additional coordination of a buffering ligand or adjuvant to a 0028. According to the current invention, the structure of metal complexed with a biologically active agent—in stark known biologically active molecules is modified to result in and dramatic contrast to what is observed in the case of new molecules known as metal coordinated complexes. salts—provides additional buffering capacity and further These new molecules have unexpectedly Superior properties. lowers the pH and/or increases the solubility of the entire 0029 Chelation is a critical component in the stabilization ofa metal coordinated complex. For the s-block metals, this is metal coordination complex, as further described below. particularly true for calcium and magnesium. For example, it 0021. Throughout this description and in the appended can be seen that the log K of the acetic acid-magnesium claims, the following definitions are to be understood: complex is 0.47. With the incorporation of a single amino 0022. The phrases "coordination complex,” “metal coor group on the molecule (i.e., glycine) the log K increased to dination complex. and the like refer to a complex of an 1.34. Magnesium typically prefers chelation with oxygen organic compound with a metal that can be empirically dif over nitrogen and this effect can be seen by comparing the log ferentiated from a simple metal salt of the organic compound K of adenine (log K 2.08) with that of 6-hydroxypurine based on physiochemical and/or spectroscopic properties, (log K-6.65). Magnesium forms particularly strong bonds with a coordination complex typically having enhanced cova with oxidized phosphorus, such as phosphates, as is revealed lency as compared to a salt. Without wishing to be bound by by comparing the log K of adenosine (log K 0.50) with a particular theory or to in any way limit the scope of the that of adenosine-5'-monophosphoric acid (log K =1.80). appended claims or their equivalents, it is presently believed 0030. In general, zinc complexes are more stable then the that a “coordination complex” in the sense used herein comparable magnesium complexes. This is particularly true involves a combination of coordinate covalent bonds and/or if the ligandbears nitrogen or Sulfur. (This may not be the case ionic bonds, whereas a metal salt is based on a purely elec for ligands with oxygen only and even less So if the ligand is trostatic attraction between a cation (e.g., a metal) and an a phosphate.) Using the glycine example above, the log K, anion (e.g., an ionized form of a biologically active agent). As for the glycine-zinc complex is 4.85. The strength of the zinc used herein, the phrase “coordination complex also includes sulfur bond versus the oxygenbond is manifest in the relative molecules that lack an ionic component (e.g., Such as a neu log K values for the zinc complexes of hydroxypropanoic tral coordination complex prior to deprotonation, where pK, acid (log K 0.86) and mercaptopropanoic acid (log K-6. of the coordination complex falls within a physiologically 43). Comparisons of log K values with other metals and acceptable range). ligands reveal that this chelation stabilization prevails in 0023 The phrase “physiologically acceptable' and the metal coordination chemistry. like as used in reference to pK values refer to pK values of 0031 Whereas it may not be required that chelation occur compounds that—when dissolved—result in Solutions hav to form a stable metal coordinated complex with inherent ing a pH value in a range from about 5 to about 9. It is to be covalency, and this is particularly true with the transition understood that the pK value perse of a compound may or metals combined with nitrogenous ligands, in most cases it is may not lie in this range although the pH of the resultant a preferred embodiment of this invention that the active agent Solution does. chelate with the metal, particularly if the metal is magnesium. 0024. The phrase “physiological pH refers to the pH of a 0032. It is an embodiment of this invention that the active patient’s blood. Typically, this pH is slightly basic (e.g., agents that make the best candidates for complexing with approximately 7.4). magnesium and calcium are those that have a proton on a 0025. The phrase “biologically active agent” refers gener heteroatom (i.e., oxygen, nitrogen or sulfur) with a pK, ally and without limitation to any compound that triggers— slightly greater than water or lower than water and have an either directly or indirectly—a physiological response in a additional heteroatom in close proximity to the first proto patient, desirably though not necessarily a therapeutically nated heteroatom Such that it can participate in the bonding, efficacious response. As used herein, the phrase “biologically or otherwise chelate, with the metal. Drugs that have this active agent' is used interchangeably with the phrase “phar arrangement of functional groups are most likely going to maceutical agent' and the term “drug.” bond with a metal, where the resultant metal coordinated US 2014/0274936 A1 Sep. 18, 2014 active agent will be stable enough in a biological system and and the p-block metals are the same as those with the s-block survive hydrolysis therein, such that the performance of the metals with the additional flexibility that if the active agent active agent will be sufficiently modulated. This hydrolytic has two nitrogens, a nitrogen and a mercaptain or two mer stability imparted by multidentate ligands is supported by the captains in a proper chelation arrangement, then the presence fact that they can lower the pK’s of the ligand such that even of a proton on a heteroatom is not necessary to form a stable amides can be deprotonated with weak bases, such as triethy metal coordinated complex. It is a further embodiment of this lamine, in the presence of coordinating metals. Therefore, invention that transition metals have further ligation flexibil active agents with protons on heteroatoms, which normally ity in that chelation is even less required for their covalent would not be ionized in typical biological pH, can have the coordination complexes if the ligands have at least one nitro proton replaced with a covalently coordinated metal, where gen or mercapto group. covalency is enhanced by the additional chelation from par 0034. The active agents which are embodied in this inven ticipating heteroatoms. It is a preferred embodiment of this tion can be divided into chemical classes as shown in Table 1 invention that at least one of the heteroatoms on the active (actually they may be divided into combinations of chemical agent that will bind to magnesium or calcium be oxygen or classes to reflect the heterogenous chelation potential). The Sulfur. Magnesium forms unusually strong bonds with phos drugs listed in Table 1 are not intended to be an exhaustive list phates and phosphonates and, therefore, it is an additional of all drugs that satisfy the embodiment of this invention but embodiment of this invention that the active agent coordi a representation of the chemical classes that exist in pharma nated with magnesium is an organophosphate or organophos ceuticals and that other pharmaceuticals that are of the same phonate compound. class listed in Table 1 or have arrangements of atoms that is 0033. It is an embodiment of this invention that the active satisfied by the embodiments of this invention are also agents that make the best candidates for complexing with Zinc claimed by this invention. TABLE 1. Biologically active molecules that form coordination complexes in accordance with the Invention. Chemical Class or Functional Group Combination Therapeutic Classes Drug Examples Guanide or diamine Antidiabetic, AntiGERD, Metformin, Famotidine, Antineoplastic, Antiviral, Mitoxantrone, Adefovir, Antihypertensive Hydralazine, Zanamivir Amine or amide with GERD, Diuretic, Famotidine, Sulfonamide Antimigraine, Antidiabetic Hydrochlorothiazide, Sumatriptan, Glipizde, Glyburide, Torsemide Amine or amide with GERD, Antiviral, Lansoprazole, Zolmitriptan, azole antimigraine, Antiurolithic, Rabeprazole, Omeprazole, Antihypertensive, Esomeprazole, Ribavarin, Analgesic, Anitemetic Allopurinol, Clonidine, Granisetron Amine or amide with Antineoplastic, Antiviral, Mitoxantrone, Saquinavir, alcohol Bone resorption inhibitor, Alendronate, Albuterol, Antibiotic, Bronchodilator, Ephedrine, Epinephrine, Antithrombotic, Analgesic, Dipyramidole, Oxycodone, Antihypertensive, Oxymorphone, Anxiolytic, Anticonvulsant Tetracycline, Minocycline, Doxycycline, Labetalol, Lorazepam, Oxazepam 3-diketone, C.-diketone, Antibiotic, Antineoplastic, Tetracycline, Minocycline, ketophenol, C.- Antiinflammatory, Multiple Doxycycline, Mitoxantrone, ketoalcohol B-ketoalcohol sclerosis treatment Atovaquone, Betamethasone, Paclitaxel, Docetaxel, Methylprednisolone, Prednisone, Idarubicin 3-ketoacid Antibiotic Levofloxacin, Ofloxacin, Norfloxacin Ureide Antiviral, Antiparkinsonian, Tenofovir, Acyclovir, Bronchodilator Cabergoline, Theophylline, Valgancyclovir Amine or amide with acid Antihypertensive, Hormone Quinapril, Ramipril, replacement, Trandolopril, Enalipril Antiparkinsonian, Diuretic, Lisinopril, Thyroxine, Antipsoriatic, Liothyronine, DOPA, Antineoplastic, Furosemide, Methotrexate, Antirheumatic, Antibiotic, Penicillin, Amoxicillin, Antiepileptic, Cefotetan, Captopril, Antidepressant, Analgesic Gabapentin, Ketorolac Alcohol with azole Angiotensin II receptor Losartan, antagonist, US 2014/0274936 A1 Sep. 18, 2014 TABLE 1-continued Biologically active molecules that form coordination complexes in accordance with the Invention. Chemical Class or Functional Group Combination Therapeutic Classes Drug Examples Phosphonate or Bone resorption inhibitor, Alendronate, Etidronate, phosphate Antiviral Fosamprenavir Phosphonate or Antiepileptic Fosphenytoin phosphate with amide Diolor polyol Bronchodilator, Nutritional Albuterol, Epinephrine, Supplements, Contrast Myoinositol, Chiroinositol, imager Iodixanol Mercaptain with acid Antiasthmatic, Antibiotic Montelukast, Cefazolin, Cefotetan Mercaptain with amine or Antipsychotic, Olanzapine, Captopril amide Antihypertensive Amine with amide Hormone deficiency, Tabimorelin, Amoxicillin, Antibiotic Loracarbef, Iodochlorohydroxyquin Alcohol with acid Analgesia, Cholesterol Salicylic acid, Atorvastatin, lowering, Antihypertensive Mesalamine, Pravastatin, Antiinflammatory Sitofloxacin, Trovafloxacin Dicarboxylic acid Antineoplastic Pemetrexed Amine with N-oxide Antiallopecia agent Minoxidi Alcohol with Nitrites Antibiotic Metronidazole Diene with alcohol, Antiacne, Antineoplastic Retinoic acid, Fenretinde amine, amide or acid Oligonucleotide Gene therapy, Anti-AMD iRNA, Pegaptainib (polyureide or polyphosphate) Oligopeptide (polyamide) Immunosuppressant, Cyclosporin, Epoetin, Antianemic, Antiviral, Inteferon, Atrial Natriuretic Antineoplastic, Diuretic Peptide, Abarelix Oligosaccharide (polyol) Anticoagulant, Antidiabetic, Heparin, Acarbose, Antibiotic Gentamycin, Tobramycin GERD = Gastroesophageal Reflux Disease AMD = Age-related Macular Degeneration 0035. As illustrated in Table 1, a suitable biologically eties that exist in pharmaceuticals or have arrangements of active moiety may have two functional heteroatom groups, atoms that satisfy the embodiments of this invention. each of which is capable of participating in the formation of a 0039. The biologically active moieties listed in Table 1 metal coordination bond. Further, as can be seen from Table 1, have the attributes that make them a member of the group in the two functional groups may be in a spatial relationship to which they are listed. They also have the functional groups each other to permitchelation to the same metal atom by those that define that group and are in close enough proximity to coordination bonds. According to a preferred embodiment, each other to be able to chelate to a metal. Each group is the coordination bond forms a 4 to 8 atom ring encompassing defined by the specific combination of functional groups the metal and the heteroatom of the functional groups and the listed. For example, a guanide is a diamine but is also a ring usually does not include a trans double bond. specific kind of diamine. A guanide can actually be consid 0036. The following discussion illustrates specific ered to be a triamine but since only two of the amino groups embodiments within the general principles discussed above. are necessary for chelating with a metal, the guanide and diamine are grouped together as a single chemical class. This 0037. Whereas it may not be required that chelation occur is the same argument for the reason beta-diketone is grouped to form a stable metal coordinated complex with inherent with beta-ketoalcohol, and diol is grouped with polyol. covalency, and this is particularly true with the transition 0040 Compounds that may be used in the embodiments of metals combined with nitrogenous ligands, in most cases it is the invention, Such as having two functional heteroatom a preferred embodiment of this invention that the biologically groups and are capable of forming stable metal coordination active moiety chelate with the metal, particularly if the metal bonds with a metal include, but are not limited to: Cladribine, is magnesium. Acetalzolamide, Eliprodil, (R.S)-3-(2-carboxypiperazin-4- 0038. The biologically active moieties that have two func yl)-propyl-1-phosphonic acid (CPP), Ifenprodil, (R)-4-oxo tional heteroatom groups that are capable of participating in 5-phosphononorvaline (MDL 100453), Dihydroxyphenylg the formation of a stable metal coordination bond are embod lycine, (S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic ied in this invention and include, but are not limited to the acid (LY367385), Eglumegad (LY354740), (2S,2R,3R)-2- biologically active moieties set forth in Table 1. The biologi (2',3'-dicarboxycyclopropyl)glycine (DCG), Remacemide, cally active moieties listed in Table 1 are not intended to be an Fingolimod, Teriflunomide, Laquinomod, Azathioprine, Clo exhaustive list of all biologically active moieties that satisfy razepate, Lorazepam, Temazepam, Rufinamide, Tiagabine, the embodiment of this invention. The examples provided in Progabide, Phenacemide, Lamotrigine, EthoXZolamide, Table 1 represent various groups of biologically active moi Zonisamide, Etoposide, Doxorubicin, Vorinostat (SAHA), US 2014/0274936 A1 Sep. 18, 2014 Bicalutamide, 7-phenyl-2,4,6-hepta-trienal hydroxamic acid, mide, Salacetamide, Salicylamide, Sapropterin, Saquinavir, Goserelin, Naltrexone, Fentanyl, Piritramide, Acadesine, Sivelestat, Sotalol, Soterenol, Stepronin, Tafenoquine, Tali Acarbose, Acebutolol, Acecarbromal, Acetylpheneturide, nolol, Taltirelin, Tegaserod, Temazepam, Temozolomide, Acitretin, Adrafinil, Albendazole, Alexidine, Aliskiren, Tenoxicam, Terbutaline, Tertatolol. Theophylline. Thiami Alprenolol. Althiazide, Alvimopan, Ambuphylline, Amcam prine. Thioguanine, Tiaprofenic Acid, Tilisolol, Tilarginine, prosate, Amfenac, Amidephrine, Amidinomycin, Amiloride, Timolol, Timonacic, Tioclomarol, Tixocortol, Tocainide, 4-Amino-3-phenylbutyric acid, Aminophylline, Amlexanox, Tolazamide, Tolbutamide, Tolcyclamide, Tolfenamic Acid, Amosulalol, Amprenavir, Arotinolol, Atorvastatin, AZidam Toliprolol, Tolrestat, Torsemide, Tretoquinol, Triamcinolone, Tulobuterol, Ubenimex, Velnacrine, Vidarabine, Vigabatrin, fenicol, Baclofen, Balsalazide, Bambuterol, Bamethan, Voglibose, Xamoterol, and Zoledronic Acid. Each compound Befunolol, Benzthiazide, Betaxolol, Bevantolol, Bisantrene, listed above has other chemical properties that may require Bitolterol, Brinzolamide, Bromfenac, Bromhexine, 5-Bro special conditions during the complexation reaction. The list mosalicylhydroxamic Acid, Bucillamine, Bucindolol, Bucu of biologically active moieties and examples set forth herein molol, Bufeniode, Bufetolol, Bufexamac, Buformin, provide a general protocol for the biologically active moieties Bufuralol, Bumadizon, Bunitrolol, Bupranolol, Buramate, listed and those related therein, but minor modifications to the Butanilicaine, Butazolamide, Butoctamide, Calcium N-Car applicable general protocols may be necessary for specific bamoylaspartate, Capreomycin, Capuride, Carazolol, Carba drugs, but are within the ordinary skill in the art. Zochrome Sodium Sulfonate, Carbimazole, Carisoprodol, Carmustine, Carteolol, Carticaine, Carubicin, Carvedilol, 0041 Preferably, compounds that may be used in the Catechin, Chloraminophenamide, Chlorguanide, Chlorphen embodiments of the invention, such as having two functional esin Carbamate, Chlorproguanil, Chlorpropamide, Choline heteroatom groups and are capable of forming stable metal Alfoscerate, Cidofovir, Clodronic Acid, Clonixin, Clo coordination bonds with a metal include, but are not limited ranolol, CloraZepic Acid, Clorprenaline, Closantel, Cynarine, to: Acetalzolamide, Vorinostat, Aliskiren, Alvimopan, Dacarbazine, Delapril, Delavirdine, Denopamine, Diazi Bicalutamide, Baclofen, Balsalzide, Brinzolamide, Chlor quone, 3.5-Dibromo-L-tyrosine, Diclofenac, Didanosine, proguanil, Diclofenac, Dorzolamide, Droxidopa, Clonixin, Dideoxyadenosine, Digitalin, Digitoxin, Dioxethedrine, Ebrotidine, Enfenamic acid, Ethylmethylthambutene, Etod Dobutamine, Docarpamine, Docetaxel, Dorzolamide, Drote olac, Flufenamic acid, Fosfosal, Lazabemide, Mefenamic banol, Droxidopa, Dyphylline, Ebrotidine, Ecabapide, acid, 6-Mercaptopurine, Melagatran, Mycopheolate mofetil, Ecgonidine, Edatrexate, Eflornithine, Ellagic Acid, Endrala Pregabalin, Quinocide, Rilmazafone, Tafenoquine, Tilargin zine, Enfenamic Acid, Entacapone, Epalrestat, Ephedrine, ine, Tolfenamic acid, Cidofovir, Didanosine, Dideoxyad Epinephrine, Erdosteine, Ergotamine, Eritadenine, Esapra enosine, Etidronic acid, Moroxydine, Nelfinavir, Pamidronic Zole, Etanidazole, Ethylmethylthiambutene, Etidronic Acid, acid, Risedronic acid and Zoledronic acid. Etodolac, Exifone, Fenbendazole, Fendosal, Fenethylline, 0042. In some embodiments, the metal is a group IIA Fenoldopam, Fenoterol, Fenpentadiol, Fentiazac, Fepradi metal, a p-block metal, a transition metal, a lanthanide or an nol, Flavopiridol, Fludrocortisone, Flufenamic Acid, actinide. In some embodiments, the metal is a group IIA metal Flunixin, Fluocortolone, Fluvastatin, Formoterol, Fosfosal, which, in Some embodiments, is magnesium, calcium or Gancliclovir, Gentisic Acid, Glafenine, Glibornuride, Gli strontium. In some embodiments, the p-block metal is a group clazide, Glimepiride, Glipizide, Gliquidone, Glisoxepid, IIIA metal, a group IVA metal or a group VA metal. In other Glyburide, Glybuthiazole, Guanabenz, Guanfacine, Hydro embodiments, the metal is a transition metal which, in some cortisone, Isoetharine, Isoflupredone, Isoladol, LaZabemide, embodiments, is a group VIII transition metal, a group IB Levobunolol, Lidamidine, Lopinavir, Lorazepam, transition metal, a group IIB transition metal, a group IIIB Lorimetazepani, Lotrafiban, Mefenamic Acid, Meglutol, transition metal, a group IVB transition metal, a group VB Melagatran, Melphalan, Mepindolol, 6-Mercaptopurine, transition metal, a group VIB transition metal or a group VIIB Metaproterenal, Methazolamide, Methisazone, Methocar transition metal. In some embodiments, the metal is a transi bamol, Methoxamine, Methylergonovine, Metipranolol. tion metal which, in Some embodiments, is a group VIII Metoprolol, Midodrine, MitoguaZone, Mitoxantrone, Mivaz transition metal. In some embodiments, the group VIII tran erol, Mizoribine, Modafinil, Mopidamol, Moprolol, Moroxy sition metal is nickel. In some embodiments, the metal is iron dine, Mycophenolate mofetil, Nadolol, Nadoxolol, Nalbu or zinc. In other embodiments, the metal is neither iron nor phine, Nalmefene, Naloxone, Nateglinide, Nebivolol. Z10. Nelfinavir, Nialamide, Nifenalol, Ninopterin, Nipradilol. 0043 Allmanner of biologically active agents are contem Nitazoxanide, Nithiazide, Nolatrexed, Nordefrin, Norepi plated for use in accordance with the present teachings— nephrine, Norfenefrine, Norpseudoephedrine, Nylidrin, preferably ones that have inadequate solubilities at physi Octopamine, Omapatrilat, Onapristone, OraZamide, ological pH and/or pK values that are physiologically Osalmid, Orotic acid, Orthocaine, Oseltamivir, Oxazepam, unacceptable, and which could potentially benefit from Oxycinchophen, Oxyfedrine, Oxymorphone, Paclitaxel, metal-coordination in accordance with the present teachings. Pamabrom, Pamidronic acid, Paramethasone, Penciclovir, Representative agents contemplated for use include but are Penicillamine, Perfosfamide, Phenazopyridine Hydrochlo not limited to the following: medicaments for treating the ride, Pheneturide, Phenformin, Phenylephrine Hydrochlo gastrointestinal (GI) tract (e.g., antacids; reflux Suppressants; ride, Phenyramidol, Phosphocreatine, Pindolol, Pipradrol, antiflatulents; antidopaminergics; proton pump inhibitors Pirarubicin, Pirbuterol, Piroxicam, Practolol, Prednylidene, (PPIs); H-receptor antagonists; cytoprotectants; prostaglan Pregabalin, Prenalterol, Procaterol, Procodazole, Proglu din analogues; laxatives; antispasmodics; antidiarrheals; bile mide, Pronethalol, Propafenone, Propranolol, Protokylol, acid sequestrants; opioids; and the like); medicaments for Pseudoephedrine, Quercetin, Quinocide, Raltitrexed, treating the cardiovascular system (e.g., B-receptor blockers; Rebamipide, Rebeccamycin, Reproterol, Ribavirin, Ril calcium channel blockers; diuretics; cardiac glycosides; anti mazafone, Risedronic Acid, Ritodrine, Romurtide, Rufina arrhythmics; nitrate; antianginals; vasoconstrictors; vasodi US 2014/0274936 A1 Sep. 18, 2014 lators; peripheral activators; and the like); antihypertension lients; anti-pruritics; antifungals; disinfectants; scabicides; agents (e.g., ACE inhibitors; angiotensin receptor blockers; a pediculicides; tar products; vitamin A derivatives; vitamin D blockers; and the like); coagulation agents (e.g., anticoagul analogues; keratolytics; abrasives; systemic antibiotics; topi lants; heparin; antiplatelet drugs; fibrinolytics; anti-hemo cal antibiotics; hormones; desloughing agents; exudate philic factors; haemostatic drugs; and the like); atherosclero absorbents; fibrinolytics; proteolytics; Sunscreens; antiper sis/cholesterol inhibitors (e.g., hypolipidaemic agents; spirants; corticosteroids; and the like); medicaments for treat statins; and the like); medicaments that affect the central ing infections and infestations (e.g., antibiotics; antifungals nervous system (e.g., hypnotics; anesthetics; antipsychotics; including but not limited to imidazoles, polyenes, etc.; anti antidepressants including but not limited to tricyclic antide leprotics; antituberculous drugs; antimalarials; anthelm intics; amoebicides; antivirals; antiprotozoals; antiparasitics; pressants, monoamine oxidase inhibitors, selective serotonin and the like); anti-inflammatory agents (e.g., NSAIDs; corti reuptake inhibitors, etc.; and the like); antiemetics; anticon costeroids; and the like); medicaments for treating the Vulsants; antiepileptics; anxiolytics; barbiturates; movement immune system (e.g., vaccines; immunoglobulins; immuno disorder drugs including but not limited to those for treating Suppressants; interferons; monoclonal antibodies; and the Parkinson's disease, etc.; stimulants including but not limited like); medicaments for treating allergies (e.g., anti-allergics; to amphetamines; benzodiazepines; cyclopyrrolones; antihistamines; NSAIDs; mast cell inhibitors; and the like): dopamine antagonists; antihistamines; cholinergics; anticho nutritional agents (e.g., tonics; iron preparations; electro linergics; emetics; cannabinoids; 5-HT Serotonin antagonists; lytes; parenteral nutritional Supplements; vitamins; anti-obe and the like); analgesics (e.g., nonsteroidal antiinflammatory sity drugs; anabolic drugs; haematopoietic drugs; food prod drugs or NSAIDs; opioids; various orphan drugs including uct drugs; and the like); antineoplastic agents (e.g., cytotoxic but not limited to paracetamol, tricyclic antidepressants, anti drugs; therapeutic antibodies; sex hormones; aromatase convulsants, etc.; and the like); medicaments for treating inhibitors; somatostatin inhibitors; recombinant interleukins; musculoskeletal disorders (e.g., NSAIDs including but not G-CSF, erythropoietin; and the like); euthanaticum agents: limited to COX-2 selective inhibitors, etc.; muscle relaxants; neuromuscular drugs; anticholinesterases; and the like); and the like; and combinations thereof. medicaments for treating the eye (e.g., adrenergic neurone 0044. In some embodiments, the biologically active agent blockers; astringents; ocularlubricants; mydriatics; cyclople is selected from the group consisting of an anticonvulsant, an gics; anti-glaucoma agents including but not limited to adr antineoplastic, and a calcium channel blocker. In some energic agonists, beta-blockers, carbonic anhydrase inhibi embodiments, the anticonvulsant is a Sulfamate which, in tors/hyperosmotics, cholinergics, miotics, some embodiments is topiramate (sold under the tradename parasympathomimetics, prostaglandin agonists/prostaglan TOPAMAX by Ortho-McNeil Neurologics). In some din inhibitors, nitroglycerin, etc.; and the like); topical anes embodiments, the antineoplastic is a histone deacetylase thetics (e.g., benzocaine; butamben: dibucaine; lidocaine; (HDAC) inhibitor which, in some embodiments, is a hydrox oxybuprocaine; pramoxine; proparacaine; proxymetacaine; amic acid. In some embodiments, the hydroxamic acid is tetracaine; and the like); sympathomimetics; parasym suberoylanilide hydroxamic acid, which is also known by its patholytics; anti-bacterial agents (e.g., antibiotics; topical generic name, Vorinostat, and which is sold under the trade antibiotics; Sulfa drugs; aminoglycosides; fluoroquinolones; name ZOLINZAby Merck Sharp & Dohme Corp. In embodi and the like); antiviral drugs; medicaments for treatment of ments in which the biologically active agent is Suberoylanil the ear, nose, and throat (e.g., sympathomimetics; antihista ide hydroxamic acid, then the metal is neither iron nor zinc. In mines; anticholinergics; NSAIDs; steroids; antiseptics; local Some embodiments, the calcium channel blocker is a dihy anesthetics; antifungals; cerumenolyti; and the like), medica dropyridine (DHP) calcium channel blocker which, in some ments for treating the respiratory system (e.g., bronchodila embodiments, is nisoldipine (sold under the tradename tors; NSAIDs; anti-allergics; antitussives; mucolytics; SULAR), nifedipine (sold under the tradenames ADALAT, decongestants; corticosteroids; B-2-adrenergic agonists; anti NIFEDICAL, and PROCARDIA), isradipine (sold under the cholinergics; steroids; and the like); medicaments for treating tradenames DYNACIRC and PRESCAL) or amlodipine diseases of the endocrine system (e.g., androgens; antiandro (sold under the tradename NORVASC). gens; gonadotropin; corticosteroids; human growth hormone; 0045. In some embodiments, the pKa of the coordination insulin; antidiabetics including but not limited to Sulfony complex is less than about 9, and in some embodiments the lureas, biguanides/metformin, thiazolidinediones, insulin, pKa of the coordination complex is in a range from about 5 to etc.; thyroid hormones; antithyroid drugs; calcitonin; dipho about 9. In some embodiments, the range is from about 6 to sponate; vasopressin analogues; and the like); medicaments about 9. In some embodiments, the range is from about 6 to for treating the reproductive system and urinary system (e.g., about 8.5. antifungals; alkalizing agents; quinolones; antibiotics; cho 0046. In some embodiments, the coordination complex linergics; anticholinergics; anticholinesterases; antispasmod further includes a buffering ligand, as explained below. In ics; 5-O. reductase inhibitor; selective C-1 blockers; sildena Some embodiments, the pKa of the coordination complex is fils; fertility medications; and the like); contraceptives (e.g., lower when the coordination complex contains the buffering hormonal contraceptives; and the like), medicaments for use ligand than when the coordination complex does not. In some in obstetrics and gynecology (e.g., NSAIDs; anticholin embodiments, the water solubility of the coordination com ergics; haemostatic drugs; antifibrinolytics; hormone plex is greater when the coordination complex contains the replacement therapy (HRT); bone regulators; B-receptorago buffering ligand than when the coordination complex does nists; follicle stimulating hormone; luteinizing hormone; not. In some embodiments, the buffering ligand provides luteinizing-hormone-releasing hormone (LHRH); gonadot additional stability to the entire coordination complex that ropin release inhibitor, progestogen; dopamine agonists; prevents the coordination complex from converting to a salt. oestrogen; prostaglandins; gonadorelin; diethylstilbestrol; 0047. In some embodiments, the buffering ligand includes and the like); medicaments for treating the skin (e.g., emol one or more hydrogen bonding sites and, in Some embodi US 2014/0274936 A1 Sep. 18, 2014 ments, the buffering ligand is selected from the group con premature infant with an immature GI tract, the metal of the sisting of an amino acid, a peptide, a carbohydrate, and a coordination complex is magnesium. Good’s buffer (e.g., MES, ADA, PIPES, ACES, cholamine 0053 Autism symptoms often appear between the ages of chloride, BES, TES, HEPES, acetamidoglycine, tricine, gly 1 and 1%, which suggests that causes occur either prenatally cinamide, and bicine). In some embodiments, the amino acid or perinatally. Contributing factors at birth may include pre is arginine, lysine or histidine. In some embodiments, the maturity, lack of oxygen to the brain, prolonged labor or buffering ligand is quinic acid, bicine, tricine, ascorbic acidor infections. In addition, low Apgar scores have been associ carnosine. ated with autism, and this association is connected to pre-term 0048. By way of further general introduction, a pharma births. Thus, in some embodiments, a metal coordinated topi ceutical Solution for treating a patient includes a coordination ramate in accordance with the present teachings is delivered complex of a type described above and water. The coordina intravenously to a pre-term infant exhibiting low Apgar tion complex is at least partially soluble in the water at physi scores in order to help prevent the onset of autism. ological pH in a therapeutically efficacious concentration. In 0054 Currently, topiramate is available only in an orally Some embodiments, the coordination complex is soluble at administered formulation, which limits its usefulness in situ least for a time sufficient to deliver the biologically active ations where oral administration is not feasible or is otherwise agent to a target site in the patient’s body. undesirable. Solutions of the drug are impractical due to the 0049 Finally, by way of further general introduction, a hydrolytic lability of neutral topiramate in water. At present, method for treating a patient includes administering a phar one of the biggest limitations on the use of oral formulations maceutical Solution of a type described above to a patient in of topiramate is in the treatment of neonates. Even if an I.V. need of the biologically active agent therein. In some embodi solution could be formulated in an appropriately low volume ments, the pharmaceutical Solution is administered to the for a 2-kg newborn baby, hydrolysis is likely to render the patient by I.P. injection, I.M. injection or I.V. injection. In product too unstable to be practical. In addition to neonates, Some embodiments, the method includes treating a neonatal an I.V. formulation of topiramate would be useful for treating seizure and the biologically active agent is topiramate. In (a) patients who, like neonates, are unable to Swallow; (b) Some embodiments, the method includes treating a cancer patients with disturbed absorption from the GI tract; (c) and the biologically active agent is Suberoylanilide hydrox patients who are undergoing GI Surgery; and (d) patients in amic acid. need of a rapid bolus of the drug. Therefore, it would be 0050. Building upon the preceding general introduction to highly desirable to formulate an aqueous solution of some coordination complexes, pharmaceutical compositions, and form of topiramate in a high enough concentration and a low methods in accordance with the present teachings, a more enough pH to enable safe I.V. administration. detailed description including specific examples is now pro 0055 Alkaline solutions of topiramate stabilize the com vided solely for the purpose of illustration—not of limitation. pound and prevent its hydrolysis. Alkaline salts oftopiramate 0051. The present inventors have investigated the prepa have shown promise in pre-clinical studies in neonatal pigs ration of chelation compounds formed between a metal ion but no successful clinical trials have been reported. Although and polydentate drug ligands. Without wishing to be bound the solubility of topiramate salts is greatly increased relative by a particular theory or to in any way limit the scope of the to the neutral drug (3.59 M vs. 0.029 M), the pH of a 0.19 M appended claims or their equivalents, it is presently believed Solution of the Salt is quite high (>10), making these salts that in these coordination complexes, the drug ligand at least unsuitable for many medical applications. In U.S. Pat. No. partially neutralizes the positive charge of the metal ion 7.351,695 granted to Ortho-McNeil, Mg, Ca, and Zn com through the formation of a combination of ionic and coordi pounds of topiramate are described but without mention of nate covalent bonds—as opposed to the purely electrostatic their detailed structures or aqueous solubilities. Investigation attraction observed in salts. While electrostatic attraction can by the present inventors has revealed these compounds to be also existin coordination complexes, the complexes addition salts. ally have an inherently covalent coordination bond between 0056 Although an I.V. formulation of topiramate has yet the metal and drug ligand. It is presently believed that this to be developed as a therapeutic option for patients, there has enhanced covalency of the coordination complex is primarily been a clinical trial in which a cyclodextrin (CD) has been responsible for reducing the pKa of its acidic protons, such used to enhance the solubility of neutral topiramate. How that Solutions of these coordination compounds are stable at ever, the potential cost of a CD derivative together with ongo physiological pH. ing regulatory and toxicology concerns over I.V. CD in neo 0052. In a first series of embodiments, the biologically nates may significantly limit CD's potential to address the active agent coordinated to a metal is topiramate. Topiramate need for an I.V. formulation of topiramate. (2,3:4,5-bis-O-isopropylidene-3-D-fructopyranose sulfa mate) is an anticonvulsant drug used to treat epilepsy in 0057 Topiramate has a pK value of 8.7 due to its weakly children and adults. It is also approved for the treatment of acidic sulfamate group. The water Solubility of topiramate is seizures associated with Lennox-Gastaut Syndrome and for about 9.8 mg/mL (0.029 M) at 23°C. but increases to about the prophylaxis of migraines. Topiramate has exhibited effec 1300 mg/mL (3.59 M) for sodium topiramate trihydrate. It tive anticonvulsant and neuroprotective properties particu has been found that coordination of the topiramate anion with larly after cerebral hypoxia ischemic events, and has been a suitable metal leads to increased aqueous solubility at lower used experimentally in the treatment of bipolar disorders, physiological pH. obesity, alcoholism, post-traumatic stress disorder, bulimia, 0058. In accordance with the present teachings, a metal obsessive compulsive disorder, Smoking addiction, and neu coordinated topiramate is used to formulate an aqueous solu ropathic pain. In some embodiments, when the biologically tion of topiramate in a high enough concentration and a low active agent is topiramate and the patient to be treated is a enough pH to allow for safe I.V. administration. In some US 2014/0274936 A1 Sep. 18, 2014 embodiments, the metal coordinated topiramate provides a Examples below, it has been discovered that any change in the heretofore unavailable treatment for neonatal seizures and ability of several metal coordinated SAHA analogs to inhibit related disease states. breast cancer cell growth as compared to SAHA itself is 0059. In general, the preferred route of administration of negligible. Thus, the ability to deliver a wide range of doses most drugs is oral, with drug developers preferring to market safely and comfortably resulting in more predictable blood oral dosage forms based on their cost, safety, and practicality. levels while minimizing drug exposure over long periods In most instances, the disadvantages of oral drug formula makes an I.V. formulation of SAHA both clinically useful and tions (e.g., decreased and highly variable bioavailability) are commercially valuable. mitigated by their advantages. One notable exception is that 0065. In U.S. Patent Application Publication No. 2009/ chemotherapy agents are traditionally administered parenter 023994.6 A1, Merck reports a chelate complex of iron or zinc ally in a physicians office or clinic. Taking oral doses outside and a SAHA ligand. However, the complexes described by Such controlled settings increases risks and requires patients Merck in contrast to those prepared in accordance with the and caregivers to assume significantly greater responsibili present teachings—were not designed to have a buffering ties. effect or to have increased solubility at physiological pH 0060. In a second series of embodiments, the biologically relative to SAHA itself. Thus, the metals Merck used to active agent coordinated to a metal is an antineoplastic agent complex with SAHA (viz., iron and Zinc) bind to SAHA too which, in Some embodiments, is Suberoylanilide hydroxamic tightly to provide the increased solubility desired in accor acid (SAHA). SAHA, which is shown in FIG. 1, was the first dance with the present teachings. In fact, the present inventors inhibitor of HDAC to be approved by the FDA and is pres have found that other transition metals—not just iron and ently indicated for the treatment of cutaneous manifestations Zinc appear to bind too tightly with SAHA and result in of cutaneous T-cell lymphoma (CTCL) in patients with pro complexes that exhibit decreased solubility, as demonstrated gressive, persistent or recurrent disease on or following two in an Example described below involving nickel metal. In systemic therapies. Since its approval in October 2006, accordance with the present teachings, it has been found that SAHA has also been found to be useful in the treatment of s-block metals are better suited for binding SAHA than tran other cancers alone and in combination with other drugs or sition metals, and are better able to impart the desired dual radiation therapy. Although HDAC inhibitors show utility in properties of lipid and water solubility. the treatment of cancers, it is to be understood that HDAC 0066. However, in some embodiments, a coordination inhibitors may also find use in non-cancer disease states. complex contains SAHA, a transition metal, and a buffering 0061. The oral bioavailability of SAHA is less than 50% ligand. In some embodiments, the additional coordination of and highly variable. Nausea and Vomiting common Symp the buffering ligand to the transition metal confers an addi toms of the disease and all too common adverse side effects of tional buffering capacity on the complex and further increases many antineoplastics—among patients exacerbates the Vari the solubility of the entire metal coordination complex, ability in this drug's bioavailability and further complicates thereby offsetting the overly tight binding of transition metals its oral administration. At present, however, SAHA is mar (e.g., iron, Zinc, and nickel) to SAHA that in the absence of keted by Merck only as an oral capsule (100 mg). An I.V. the buffering ligand-can result in inadequate Solubilities. formulation would provide certain advantages over peroral 0067. In a third series of embodiments, the biologically formulations, especially with cancer and other patients that active agent coordinated to a metal is a DHP calcium channel may suffer from GI upset. blocker. DHP calcium channel blockers, which are consid 0062 SAHA is a relatively lipophilic molecule having ered BCS Class II drugs, are practically insoluble in water (-1 limited water solubility of about 0.1 mg/mL. In a prior study ug/mL). Their low bioavailability is also due to extensive aimed at increasing its solubility, the sodium salt of SAHA oxidative metabolism by cytochrome P450 enzymes in the was prepared at Memorial Sloan Kettering Cancer Center but intestinal epithelia. required solution pH values above 11—that is, two units 0068. The pKa of DHP calcium channel blockers typically above the maximum pH level (-9) usually observed for intra ranges between about 9 and about 10, which means that the venous dosing in order to stay in solution. In addition, the salts of these compounds will be soluble in water but only at Solution required slow administration over a two hour period a pH well above a physiologically relevant value. Lowering in order to provide sufficient dilution to minimize irritation at the pH of an aqueous solution of the salt of a DHP drug will the injection site. result in its precipitation. Thus, there is a need for a formula 0063. In another study, workers used 2-hydroxypropyl-B- tion by which a DHP calcium channel blocker can be stabi cyclodextrin (HOP-B-CD) at a molar concentration five times lized Such that its migration from a drug delivery vehicle to a that of SAHA in an effort to enhance the latter’s aqueous target site is facilitated Sufficiently to enable maximum drug solubility and to enable administration of the drug in drinking absorption. water. However, cyclodextrins are expensive and not as bio 0069. In accordance with the present teachings, the solu logically friendly as simple pH adjustment. In addition, there bility of a DHP calcium channel blocker, such as nisoldipine, remains skepticism within regulatory agencies—particularly is increased by forming a stable metal coordination complex the FDA-concerning the intravenous use of cyclodextrins. thereof, which would facilitate the drug’s migration from a 0064 Hydroxamic acid HDAC inhibitors typically have a delivery vehicle (e.g., a GEOMATRIX tablet) to the microvil pK value of about 9.2. In accordance with the present teach lus lining, after which the metal coordination complex would ings, a metal coordinated SAHA is used to formulate an revert back to its neutral form due to the lower pH of between aqueous solution of SAHA in a high enough concentration about 5 and about 6 of the aqueous unstirred layer on the and a low enough pH to allow for safe I.V. administration. As surface of the microVilli. The neutralized nisoldipine would shown in an Example below, the solubility of SAHA in water now be associated with the epithelial cell membranes and at near physiological pH was increased ~19-fold for a Ca(SA absorption of the drug could ensue. Since DHP calcium chan HA)(quinic acid) analog. Moreover, as further shown in the nel blockers have very similar structures and pKa values, the US 2014/0274936 A1 Sep. 18, 2014 mechanism of stable metal coordination complex migration ings—whether or not the coordination complex contains a described above can be applied to other DHP calcium channel buffering ligand—involves ligand polarization enhancement. blockers. 0075 According to the theory of ligand polarization 0070 The present teachings are not to be construed as enhancement, coordination of a ligand to a positively being limited to a single drug delivery technology. For charged metal center will result in development of a positive example, any drug delivery technology that provides con charge on the ligand donoratom or functional group, Such that trolled release of a pharmaceutical and/or targeted delivery of any group attached to the donor atom capable of leaving as a a drug to a specific site is contemplated for use in accordance cation will have its leaving group capacity enhanced through with the present teachings. Representative technologies metal coordination. Thus, the pKa of protic acids will be include but are not limited to GEOMATRIX (U.S. Pat. No. typically lowered upon coordination (e.g., by ~2 pK units). 5,422,123), cylindrical plug (U.S. Pat. No. 7, 195,778), For example, when the biologically active agent/ligand is OROSR), and technologies described in U.S. Pat. Nos. 6,375, topiramate (tpm), the donor atom is the Natom of the sulfa 978 B1; 6,368,626 B1; 6,342,249 B1; 6,333,050 B2: 6,287, mate group, and the leaving cation is a proton, thereby gen 295 B1; 6,283,953 B1; 6,270,787 B1; 6,245,357 B1; and erating the tipm ligand as shown in FIG. 2. This phenom 6,132,420. The entire contents of each of the above-identified enon—combined with the fact that weaker bases can U.S. patents are incorporated herein by reference, except that participate in chelate forming reactions—means that metal in the event of any inconsistent disclosure or definition from coordination complexes form molecules that are less basic the present specification, the disclosure or definition herein than organic salts. shall be deemed to prevail. 0076. In embodiments in which a buffering ligand is 0071. In a fourth series of embodiments, a coordination included in the coordination complex of a metal and a bio complex in accordance with the present teachings further logically active agent, the metal is selected Such that other includes a buffering ligand/adjuvant. It is to be understood ligands can be attached to the metal:drug complex (i.e., the that in any of the embodiments described herein—regardless metal has more than 2 binding sites). In some embodiments, of the metal and/or biologically active agent (e.g., topiramate, the metal is able to adopt a square planar or other 4-binding or SAHA, DHP calcium channel blocker, etc.)—a buffering 5-binding site geometry. In some embodiments, the metal is ligand is optionally included in the coordination complex. In able to adopt octahedral geometry. In some embodiments, the Such embodiments, the biologically active agent forms a metal is generally recognized as safe (GRAS) by the FDA. In stable complex with a metal having the capacity to bind more Some embodiments, the metal is magnesium, calcium, stron than one ligand with at least one of the additional ligands tium or zinc. having a pH buffering capacity. In some embodiments, the 0077. In some embodiments, the buffering ligand is buffering ligands formally donate electrons to the metal to selected from a group of molecules that (a) form stable com form an electrostatic interaction or bond and/or donate elec plexes or chelates with the metal and (b) have a buffering trons through a metal coordination bond. Traditionally, che capacity such that the entire complex has a pK, within a lation compounds refer to a metallic ion bonded to one or physiological acceptable range of about 5 to about 9 (in some more chelating ligands, wherein a chelating ligand is a poly embodiments from about 6 to about 8.5). In some embodi dentate ligand capable of two or more points of attachment to ments, the buffering ligand is an amino acid which, in some the metal ion (e.g., two or more donor atoms) to form a embodiments, is arginine, lysine or histidine. heterocyclic ring structure. 0078. In some embodiments in which a buffering ligand is 0072 A sulfamate, HDAC inhibitor, or DHP calcium included in the coordination complex, the metal, the biologi channel blocker used as the biologically active agent of a cally active agent, and the buffering ligandare part of a single coordination complex in accordance with the present teach molecular entity, Such that the entire coordination complex ings can provide a ligand in which one atom is tightly bound retains its structural integrity at physiological pH for a period to the metal while other atoms provide minor contributions to of time sufficient to allow I.V. administration and/or migra metal chelation. The bond between particular metals and tion from a drug delivery vehicle to target tissue. In addition biologically active agents imparts Some covalency—as to the stability provided to the coordination complex by its would be conferred in a coordination complex—in addition to ionic and coordination bonds, other forces including but not Some ionic character—as would be conferred in a salt. The limited to hydrogen bonding and/or Van der Waals attrac combination of these properties confers onto the coordination tions—especially between the buffering ligand and the bio complex an ability to retain solubility at relatively high con logically active agent—can also contribute to the overall sta centrations at physiological pH. bility of the coordination complex. 0079. In some embodiments in which the coordination 0073. The solubility of coordination complexes is influ complex contains a buffering ligand and the biologically enced by various interacting factors that involve composition active agent is topiramate or an HDAC inhibitor, the coordi and structure including but not limited to the nature of the nation complex is stable in water at least long enough for it to metalion, the symmetry of the molecule, the redistribution of be injected as a solution. Thus, sterile water is added to a electron density in ligands upon complexation, and/or the powder of a coordination complex containing a buffering conformation of coordinated ligands. As a guideline, the ligand, a solution formed, and the resultant solution injected higher the lipophilicity or hydrophilicity of the ligands into a patient before precipitation of the complex becomes involved in chelation, the higher the corresponding lipophi problematic. Thus, through a combination of metal coordina licity or hydrophilicity of a coordination complex. tion, buffering to lower pK, and slowed kinetics of precipi 0074. Without wishing to be bound by a particular theory tation, a coordination complex in accordance with the present or to in any way limit the scope of the appended claims or their teachings provides a stable, water-soluble form of a drug that equivalents, it is presently believed that the lowering in pH of would otherwise have been exceedingly difficult and/or a coordination complex in accordance with the present teach impossible to prepare. US 2014/0274936 A1 Sep. 18, 2014 0080 FIG.3 shows two coordination complexes embody ing features of the present teachings in which the biologically tpmH 1. KOH, THF Ca?tpm) active agent is topiramate, the metal is magnesium, and the 2. Ca(OAc)2, MeOH coordination complex either lacks (i.e., the coordination com plex on the left) or includes (i.e., the “mixed ligand' coordi nation complex on the right) a buffering ligand (e.g., the I0084. Second, in the preparation of a coordination com amino acid histidine). In the “mixed ligand coordination plex that contains a buffering ligand, parameters such as complex shown on the right in FIG.3, a buffering ligand (i.e., Stoichiometry, order of reagent addition, solvent, tempera histidine) replaces one of the topiramates of the coordination ture, concentration, purity of solvents and/or reagents, and the complex on the left. In some embodiments, the buffering like should be controlled. Within these parameters, the prepa ligand is an adjuvant capable of improving the Solubility of a ration of a coordination complex that contains a buffering biologically active agent at low pH. One factor that enhances ligand can be achieved by a synthetic route including but not the aqueous solubility of a coordination complex is its ability limited to the following, as depicted schematically in the to hydrogen bond with a solvent. Thus, a coordination com corresponding reactions (1)–(4) below: (1) simultaneous plex that contains a buffering ligand capable of forming combination of the biologically active agent (L) and buffering hydrogen bonds is generally more soluble in polar protic ligand (L'); (2) sequential combination of the ligands L and Solvents because of the increased energy of solvation. Amino L'; (3) coproportionation reaction between two binary bis acids, peptides, and carbohydrates—including but not limited ligand (or homoleptic) complexes; and (4) Substitution reac to those shown in FIG. 4.—are three representative types of tion in which a ligand in a metal complex is replaced by a biocompatible buffering ligands that can be used in accor second ligand (a reaction that depends on thermodynamic dance with the present teachings. stability of the ligand binding with the metal ion and on the 0081. In some embodiments, the buffering ligand is an reaction mechanism). amino acid. In general, amino acids have powerful chelating M--L--L' MLL" (1) properties, are readily available, and exhibit diverse physico chemical properties. In some embodiments, the amino acids MLL'RFMLL' (2) are protonated at physiological pH to increase water solubil ML2+ML' 2 MLL (3) ity and to act as intramolecular buffers. In some embodi ments, the buffering ligand is a carbohydrate. Carbohydrates ML2+L' MLL'+L (4) are configured for enhancing the water solubility of a coor 0085. In a solution containing a metal ion and ligands L dination complex, and acidic carbohydrates (e.g., ascorbic and L', the formation of the mixed ligand complex MLL is acid) are configured to lower the pH of a coordination com more favored on a statistical basis than the formation of the plex in Solution. In some embodiments, the biologically binary complexes ML and ML. The equilibrium constant active agent is topiramate and the buffering ligand is ascorbic for the formation of the mixed ligand complex is related to the acid. In some embodiments, a coordination complex in accor equilibrium constant of the corresponding coproportionation dance with the present teachings includes a buffering ligand reaction (reaction3 above), K. If statistical factors alone wherein the buffering ligand facilitates transport of a biologi were responsible for formation of the mixed ligand complex, cally active agent to a target site (e.g., a specific organ and/or then K would equal 4. However, since the experimental tissue) in a patient. values of K differ from the statistical value, other factors 0082. The synthetic route by which a coordination com are involved in the formation of mixed ligand complexes. plex in accordance with the present teachings—whether or These factors include electronic, electrostatic, and steric not it further contains a buffering ligand is prepared is not effects that can affect product formation by stabilizing or restricted. However, for purposes of illustration, some repre destabilizing the complexes. sentative approaches, which are not to be construed as limit I0086. As further shown in the examples below, a coordi ing and/or the only available routes, are now described. nation complex that contains topiramate as its biologically 0083 First, the preparation of a coordination complex that active agent and an amino acid as a buffering ligand has been does not necessarily contain a buffering ligand can be prepared using the coproportionation approach, shown in achieved by a synthetic route including but not limited to the reaction (3) above. Other mixed ligand coordination com following: (1) reacting an acidic ligand having additional plexes have also been prepared using the coproportionation donoratoms with a strong base in water to form a salt, which approach as shown in the examples below: is then reacted with a metal salt usually in the form of a halide or an acetate—in an organic solvent; and (2) reacting an acidic ligand having additional donor atoms with a metal lic base such as Mg(t-butoxide), Ca(OMe), or Zn(i-pro poxide) in an organic solvent. As further shown in the examples below, a coordination complex containing topira Ca(saha) + Ca(tricine);2A Ca(saha)(tricine) mate and either magnesium or Zinc metal has been prepared by method (1), while a coordination complex containing topi Ca(saha) + Ca(quintano), 22 Ca(saha) (quintano) ramate and calcium metal has been prepared by method (2). Moreover, it should be noted that a key principle in favoring the formation of a coordination complex of an organic com I0087. Of course, it is to be understood that the copropor pound and a metal as opposed to a salt is to prepare the tionation reaction shown above is only one representative complex in a non-aqueous system, such as shown in the approach to preparing a coordination complex containing a following representative reaction in which the biologically buffering ligand and that other synthetic approaches are also active agent is topiramate: viable. US 2014/0274936 A1 Sep. 18, 2014 0088 As explained above, a coordination complex in 0094. The distribution coefficient is not a constant value accordance with the present teachings is different than a and will vary according to the protogenic nature of the mol simple metal salt. The differentiation of coordination com ecule. Log D (logo of the distribution coefficient) at pH 7.4 is plexes and simple salts can be achieved by various methods often reported to give an indication of the lipophilicity of a including but not limited to: "H and C nuclear magnetic drug at the normal pH of blood plasma. A log D value of 2.0 resonance (NMR) spectroscopy; two-dimensional NMR is considered optimal for crossing the blood-brain barrier. For techniques, such as Diffusion Ordered Spectroscopy topiramate, for example, the log D value is -0.5. However, (DOSY) NMR; differentiating physiochemical properties despite this relatively low value, topiramate appears to readily (e.g., solubility and/or distribution coefficients); infrared (IR) cross membranes. spectroscopy; mass spectrometry; molar conductivity; mag 0.095 Without wishing to be bound by a particular theory netic measurements; and X-ray crystallography. or to in any way limit the scope of the appended claims or their I0089 Structures can be determined using H and/or 'C equivalents, it is presently believed that increasing log D by NMR spectroscopy through a comparison of chemical shifts, coordinating a ligand with a metal—although it may seem coupling constants, and/or changes of relaxation parameters counterintuitive—is consistent with the formation of a coor caused by coordinate covalent bond formation as compared to dinate covalent bond between a metal and a ligandanion, and a reference drug ligand (e.g., topiramate). As shown in the Supports a contention that metal coordination leads to examples below, the magnitude of the change in chemical amphiphilic drugs. Without wishing to be bound by a particu shift in the "H NMR spectra of a metal-coordinated topira lar theory or to in any way limit the scope of the appended mate is not similarly observed in the case of a simple salt. claims or their equivalents, it is further believed that metal coordination in accordance with the present teachings will 0090 Coordination complexes in accordance with the not significantly lower a drugs log D or adversely affect its present teachings can be evaluated on the basis of Solubility ability to penetrate the BBB. Furthermore, for a coordination measurements, distribution coefficients, stability measure complex in which the biologically active agent is topiramate, ments, etc. A description of each of these types of measure it is expected that the bond between the metal and topiramate ment is given below. will dissociate prior to transport across the BBB due to cir 0091 Solubility: Intrinsic solubility (WS) is defined as culating proteins and minerals in the bloodstream. Thus, the number of moles per liter of solute that dissolves into coordination complexes in accordance with the present teach Solution. Equilibrium between Solute and Solution is main ings—whether or not they contain a buffering ligand—should tained at a specific temperature (usually 25°C.). For a neutral perform within the body at least as well as the reference drug compound, the total solubility equals the intrinsic solubility itself. because only the neutral compound is involved. However, for 0096 Stability: In some embodiments, a coordination a compound with ionizable groups, the solubility expression complex in accordance with the present teachings (e.g., one in is more complex because multiple species with varying solu which the biologically active agent is topiramate) does not bilities are present. Accordingly, it is necessary to use the term revert back to the biologically active agent in aqueous solu aqueous solubility (WS) to define the solubility of com tion before the solution is administered to the patient. How pounds having ionizable groups. Aqueous solubility is the ever, once the coordination complex has been delivered to the sum of the individual solubilities for the neutral compound blood, it is anticipated that that the coordination complex will and all ionized species present. For compounds having ion dissociate (although, by that point, sufficient dilution will izable groups, aqueous solubility is a function of pH. Given have occurred Such that the biologically active agent will WS (the solubility of the neutral compound) and the solubil remain dissolved). In typical nursing/pharmacy operations, ity of each ionized species (C), the equation for aqueous powders are reconstituted prior to use and administered solubility becomes: within approximately 10 minutes of dilution. In some embodiments, integrity of the coordination complex is main tained at or above 90% for at least 30 minutes. 0092 A pH-solubility profile is a set of solubility values at 0097. The following examples and representative proce specified pH values. The values given in a pH profile refer to dures illustrate features in accordance with the present inven solubility as a function of pH for all species of a compound tion, and are provided solely by way of illustration. They are (ionizable and neutral) in solution. Solubility profiles can be not intended to limit the scope of the appended claims or their used to delineate solubility in complex situations where mul equivalents. tiple ionizable species are present. 0093. Distribution Coefficients: Due to the inherent cova EXAMPLES lency associated with coordination complexes, penetration of 0.098 Synthesis of Calcium(topiramate): To a 10-mL the blood-brain barrier (BBB) by the coordination complex round-bottomed flask equipped with magnetic stirrer was after its administration into the bloodstream is facilitated. added potassium topiramate (249.8 mg, 0.661 mmol). Anhy Indeed, in some embodiments, penetration of the BBB is drous methanol (5 mL) was added via Syringe and the Solid particularly desirable. Such as in treatments for brain cancer dissolved. Calcium acetate (52.9 mg, 0.330 mmol) was added (e.g., using a biologically active agent Such as topiramate or and dissolved with stirring. The solution was stirred at room an HDAC inhibitor). The BBB permeability of coordination temperature for 16 hrs. Solvent was removed under reduced complexes in accordance with the present teachings can be pressure affording a white solid in quantitative yield. "H predicted by measuring their distribution coefficients. The NMR (DMSO-d): 84.55 (dm: J=7.8 Hz: 1H: H4), 4.29 (m; distribution coefficient (D) is the ratio of un-ionized com 1H: H3), 4.21 (br. d: J=8.0 Hz; 1H: H5); 3.75-3.66 (m; 3H; pound in the lipid phase to the total in the aqueous phase as H1 a,b,6a), 3.55 (br. d: J=13.2 Hz: 1H: H6b), 1.43 (s; 3 H: given by: CH); 1.35 (s; 3H; CH), 1.34 (s; 3H: CH), 1.27 (s; 3H: D=un-ionized (o) fun-ionized (aq)+ionized (aq) CH). Ca 4.2% (theoretical 4.4%). This material (32 mg US 2014/0274936 A1 Sep. 18, 2014 based on topiramate) was dissolved in HO (1 mL) and the pH 0105 Synthesis of Zinc(topiramate)(arqinine): To a 5-mL adjusted to 7.0 by the addition of 1.0 NHC1. No precipitate vial equipped with magnetic stirrer were added Zinc topira was observed upon standing for 2 hours. mate (25.4 mg., 0.034 mmol) and anhydrous dimethylaceta 0099. As a point of reference, the "H NMR data for topi mide (2.5 mL) via Syringe. To this solution was added Zinc ramate (DMSO-d) are as follows: 8 4.61 (dd: J=7.8, 2.4 Hz: arginate (14.1 mg, 0.034 mmol) and the mixture was stirred to 1H: H4), 4.25 (br. d: J=8.0 Hz; 1H: H5); 4.24 (d: J=2.0 Hz: homogenize. An aliquot (1 mL) was syringed into an 1H: H3), 4.01 (d: J=10.0 Hz; 1H: H1a), 3.96 (d: J=10.0 Hz: ampoule, which was sealed and heated at 102° C. for 16 1H: H1b), 3.75 (d: J=12.8 Hz: 1H: H6a), 3.62 (d: J=12.8 Hz, hours. Solvent was removed under reduced pressure afford 1H, H6b), 1.47 (s; 3 H; CH,); 1.37 (s;3H:CH), 1.34 (s;3H: ing a white solid. "H NMR: (DMSO-d): 85.08 (m; 1H: NH), CH), 1.28 (s; 3H: CH). 4.57 (brid: J=8.0Hz; 1H:T4), 4.27 (s; 1H:T3); 4.21 (d: J=8.4: 0100 Calcium Salt of Topiramate: To a 10-mL beaker 1H: T5), 3.73 (d: J=12.8 Hz: 1H: T6a), 3.54 (d: J=11.6; 1H: equipped with magnetic stirrer, topiramate (50 mg, 0.147 T6b), 3.45-3.30 (m; 3H; T1a,b A2), 3.08 (m; 2H; A5); 1.79 mmol) was suspended in 2 mL of water with stirring. KOH 1.72 (m; 1H: A3a), 1.60- 1.48 (m, 3H; A3b, A4a,b), 1.44 (s; (147 uL. 147 umol) was added as a 1.0 Naqueous solution. 3H; T CH3), 1.34 (s; 6H; 2x T CH3), 1.27 (s; 3H; T CH3). The topiramate mostly dissolved with gentle heating. Cal 0106. As a point of reference, the "H NMR data for cium acetate (11.63 mg, 0.0735 mmol) was added. The solu Zn(tpm) (DMSO-d) are as follows: 6 4.56 (dd: J=7.8, 2.0 tion was stirred overnight. The slightly cloudy Suspension Hz: 1H: T4), 4.28 (d: J=2.0 Hz; 1H: T3), 4.22 (d: J=8.0 Hz: was filtered to remove any unreacted topiramate. The water 1H: T5); 3.93 (d: J=10.4 Hz: 1H: T1a), 3.82 (d: J=10.4 Hz: was removed from the filtrate under reduced pressure afford 1H: T1b), 3.73 (d: J=12.8 Hz: 1H: T6a), 3.57 (d: J=12.8 Hz, ing 43.7 mg of a white solid. "H NMR (DMSO-d): 8 4.59 1H, T6b), 1.44 (s; 3H, CH3); 1.37 (s; 3H, CH3), 1.34 (s; 3H; (dd: J=7.8, 2.4 Hz: 1H: H4), 4.25 (d: J=2.0 Hz: 1H: H3), 4.24 CH3), 1.27 (s;3H:CH3). As a point of reference, the "H NMR (br. m: 1H: H5); 3.96 (d: J=10.0Hz; 1H: H1a), 3.91 (d: J=10.0 data for Zn(arg), (DMSO) are as follows: 83.34 (bris; 1H: Hz: 1H: H1b), 3.75 (d: J=12.8 Hz: 1H: H6a), 3.60 (d: J=12.8 A2), 3.12 (bris; 2H; ASa,b), 1.78 (bris; 1H: A3a), 1.56 (brs: HZ, 1H, H6b), 1.46 (s; 3 H; CH); 1.36 (s; 3H: CH), 1.34 (s; 3H; A3b A4a,b). 3H; CH), 1.28 (s; 3 H; CH). 0101. The compound obtained displayed a "H NMR dif 0107 Of particular significance are the observations in the fering significantly from the coordination complex especially H NMR of the mixed ligand coordination complex that H3 of comparing the chemical shifts of protons 1a and 1b. A sample topiramate collapses from a doublet (J-2.0 Hz) to a singlet, of this material (32 mg based on topiramate) was dissolved in and that H4 collapses from a doublet of doublets to a doublet. H2O (1 mL) and the pH adjusted to 7.0 as above. A precipitate Without wishing to be bound by a particular theory or to in formed immediately which was identified after filtration as any way limit the scope of the appended claims or their topiramate. equivalents, it is presently believed that this is evidence of a ring conformational change caused by an intramolecular 0102. A comparison of the above results clearly shows a ligand-ligand interaction between topiramate and arginine in difference in physicochemical properties between a salt and a the ternary coordination complex, which is not observed for coordination complex. the Na, K or Casalts or Zn coordination complex. A similar (0103) Synthesis of Magnesium (topiramate). To a 5-mL phenomenon with respect to the coupling of H3 in topiramate conical vial equipped with magnetic stirrer was added potas is observed for Ca(tpm), the homoligated compound (binary sium topiramate (120 mg, 0.317 mmol). Anhydrous methanol complex), although the effect is not as large. In this case, the (2.5 mL) was added via Syringe and the Solid dissolved. ligand-ligand interaction is influenced by the differential Magnesium acetate (37.8 mg, 0.176 mmol) was added and binding affinity of the metal. dissolved with stirring. The solution was stirred at room tem perature for 16 hrs. Solvent was removed from the solution 0.108 Solubility/pH Studies of Topiramate-Containing under reduced pressure yielding white solid. "H NMR Coordination Complexes: Initial screening of drug candi (DMSO-d): & 4.56 (dd: J=8.0, 2.4 Hz: 1H), 4.28 (d: J=2.4 dates was based on a qualitative determination of aqueous Hz: 1H), 4.22 (br. d: J=8.0Hz; 1H); 3.80 (d: J=14.8; 1H), 3.80 solubility using gravimetric methods. Briefly, a known quan (d: J=14.8 Hz: 1H), 3.76 (d: J=14.8 Hz: 1H), 3.73 (d: J=13.2 tity of coordination compound (ca. 50mg) was dissolved in a Hz: 1H), 3.56 (d: J=13.2 Hz: 1H), 1.44 (s; 3H); 1.35 (d: J=5.2 known amount of water (1000/L). The pH of the resulting Hz: 6H), 1.27 (s; 3H). 'C NMR (DMSO-d): & 113.22, mixture was measured, and the solution/suspension was fil 113.02, 106.80, 75.33, 74.72, 72.27, 65.49, 53.73, 31.48, tered and concentrated to afford a minimal solubility value. 30.95, 30.45, 29.23. Using this method, it was found that the solubility of 0104 Synthesis of Magnesium(topiramate) (histidine): To Ca(tpm) is a 34 mg/mL at pH 7.0 which—Surprisingly and a 1-mL ampoule were added magnesium topiramate (15.0 unexpectedly is at least three times the solubility of free mg, 0.021 mmol), magnesium histidine (6.0 mg, 0.018 topiramate (9.8 mg/mL). mmol), and water (1.0 mL) via pipette. The ampoule was 0109 Synthesis of McCsaha): To a 25-mL round-bot sealed and heated at 100° C. for 16 hours. Solvent was tomed flask equipped with magnetic stirrer, heating mantle, removed under reduced pressure affording a white solid. "H and reflux condenser was added saha (100 mg. 0.379 mmol). NMR: (DO): 8 7.74 (s; 1H2), 7.04 (s; 1H: H4), 4.48 (dd: Anhydrous methanol (10 mL) was added via Syringe and the J=12.8 Hz, 4.8 Hz: 1H:T4), 4.43 (d: J=2.2 (ay.); 1H:T3), 4.21 solid dissolved. Magnesium acetate (40.6 mg, 0.189 mmol) (d: J=5.2 Hz: 1H: T5), 3.99 (d: J=13.6 Hz: 1H: T6a); 3.94 (d; was added in one portion and immediately dissolved. The J=6.4; 1H: T1a), 3.92 (d: J=6.4 Hz: 1H: T1b), 3.78 (d: J=13.6; solution was refluxed for 16 hrs. Solvent was removed from 1H: T6b), 3.67 (dd: J=26.4 Hz, 12.4 Hz: 1H: H7), 3.19 (dd: the clear Solution under reduced pressure yielding a colorless J=13.0 Hz (av.), 7.8 Hz (av.); 1H: H6a); 3.08 (dd: J=15.0 Hz solid. The aqueous solubility was determined by UV-VIS (ay.), 7.0Hz (ay.); 1H: H6b), 1.59 (s.3H:TCH), 1.50 (s;3H: spectroscopy (242 nm in MeCH) to be 0.40 mg/mL at pH TCH), 1.45 (s; 3H; T CH), 1.42 (s; 3H; T CH). 7.75. 'C NMR (DMSO-d): & 1717, 139.8, 136.6, 129.0, US 2014/0274936 A1 Sep. 18, 2014 123.3, 119.4, 36.8, 28.8, 25.4. Note: The CNMR chemical TABLE 2-continued shifts for the carbonyl carbons of SAHA are 171.7 and 169.5 ppm. Compound Water Solubility 0110. Synthesis of Ca(tricine): Tricine (250 mg, 1.40 No. Compound (mg/mL) pH mmol) and water (7 mL) were added to a 10-mL vial. Barium 2 Ca(saha)2 O45 8.6 hydroxide (133 mg, 0.70 mmol) was added to this solution in 3 Ni(saha) O.04 5.67 one portion. The clear solution was stirred for 30 minutes at 4 Ca(saha) (tricine) 1.41 8.75 room temperature. CaSO (121 mg, 0.70 mmol) was added in 5 Ca(saha) (quinic acid) 1.86 8.25 one portion. A precipitate formed immediately. The Suspen sion was stirred an additional 1 hour. The mixture was 0117. As shown in Table 2, the sodium salt of SAHA vacuum filtered using medium porosity filter paper. Solvent shows a nearly 7-fold increase in solubility over SAHA itself was removed under reduced pressure leaving 278 mg (0.7 although the pH of the solution of this salt is 10 well above mmol. 100% yield) of Ca(tricine), as a colorless solid. the acceptable range for an I.V. formulation. However, Sur 0111 Synthesis of Ca(saha): SAHA (50 mg, 0.19 mmol) prisingly and unexpectedly, metal coordination of SAHA and anhydrous methanol (2 mL) were added to a 2-mL with ans-block metal increased its solubility to approach that ampoule. Calcium acetate (15 mg, 0.10 mmol) was added in of the unusable Sodium salt but at a much lower, physiologi one portion. The ampoule was sealed and the solution was cally acceptable pH. Moreover, incorporating adjuvants such refluxed for 16 hrs. Solvent was removed under reduced pres astricine and quinic acid into the coordination complex yields Sure leaving a colorless solid. The aqueous solubility was products that—Surprisingly and unexpectedly—exhibit both determined by UV-VIS spectroscopy (242 nm in MeOH) to a therapeutically relevant solubility and a therapeutically be 0.45 mg/mL at pH 8.60. acceptable pH, thus providing effective and safe I.V. formu 0112 Synthesis of Ca(saha)(tricine): Ca(saha) (25 mg, lations for SAHA. 0.04 mmol) and anhydrous DMSO (2 mL) were added to a 0118. As noted in the description above and as evidenced 2-mLampoule. Ca(tricine) (18 mg, 0.04 mmol) was added in by the solubility data for compound 3 shown in Table 2, a one portion. The ampoule was sealed and the solution was complex of SAHA coordinated with a transition metal (viz., heated at 65° C. for 16 hrs. Solvent was removed under Ni) as opposed to an S-block metal (e.g., Mg or Ca) results in reduced pressure leaving a colorless solid. The aqueous solu a complex that is even less soluble than SAHA itself a bility of this compound was determined by UV-VIS spectros reduction in solubility that, based on present understanding, copy (242 nm in MeOH) to be 1.4 mg/mL at pH 8.75. is attributable to the fact that transition metals bind SAHA too 0113 Synthesis of Ca(quinic acid): Quinic acid (150 mg, tightly (i.e., confer too much covalency to the complex). 0.781 mmol) and DMSO (5 mL) were added to a 25-mL 0119. As shown in Table 2, the pH of a solution of round-bottomed flask. Calcium methoxide (39.8 mg, 0.391 Ca(saha) (compound 2) is actually slightly higher than the mmol) was added in one portion. The clear Solution was pH of a solution of SAHA itself. However, this increase in pH stirred for 16 hours at room temperature. Solvent was is not to be automatically construed as reflecting a corre removed under reduced pressure leaving a colorless Solid. sponding increase in pK. The distinction can be explained as 0114 Synthesis of Ca(saha)(quinic acid): Ca(saha) (20 follows and is worth bearing in mind when evaluating the data mg, 0.035 mmol) and anhydrous DMSO (2 mL) were added in Table 2. First, references to pK, refer to the pKa of a proton to a 2-mL ampoule. Ca(quinic acid) (15 mg, 0.035 mmol) attached to a neutral or fully protonated biologically active was added in one portion. The ampoule was sealed and the agent or a metal-coordinated biologically active agent. How solution was heated at 65° C. for 16 hrs. Solvent was removed ever, in the case of a metal-coordinated biologically active under reduced pressure leaving a colorless Solid. The aqueous agent such as Ca(saha), the SAHA moiety is deprotonated solubility of this compound was determined by UV-VIS spec relative to SAHA itself. The pH of the deprotonated salt of troscopy (242 nm in MeOH) to be 1.86 mg/mL at pH 8.25. SAHA is around 10 as revealed by Na(saha). Therefore, the 0115 Synthesis of Ni(saha): To a 25-mL round-bottomed pH of a solution of Ca(saha) does not necessarily reflect the flask equipped with magnetic stirrer, heating mantle, and pK, of the corresponding protonated species. reflux condenser was added SAHA (100 mg, 0.379 mmol). I0120 Anticancer Activity Testing: To test whether the Anhydrous methanol (10 mL) was added via Syringe and the incorporation of SAHA into a coordination complex affects solid dissolved. Nickel acetate (47.2mg, 0.189 mmol) was its anticancer activity, cell proliferation assays were con added in one portion and dissolved with stirring. The solution ducted. In the experiment, MDA-MB-231 breast cancer cells was refluxed for 16 hrs. Solvent was removed from the green were plated (500 cells/well) on a 96-well plate and grown in Solution under reduced pressure yielding green Solid. The culture for 24 hours. Drug solution was added and the cells aqueous solubility was determined by UV-VIS spectroscopy were incubated for 48 hours. The drug medium was removed (242 nm in MeOH) to be 0.04 mg/mL at pH 5.86. and the number of cells determined using the MTS method. 0116 Solubility and pH Testing: Table 2 below shows data As shown in FIG. 5, the data demonstrate that SAHA-con for the solubility of SAHA, the sodium salt of SAHA, and five taining coordination complexes inhibit breast cancer cell metal coordinated complexes of SAHA. growth at concentrations (2.5-5 mM) for which SAHA is active. TABLE 2 0121 The foregoing detailed description and accompany Compound Water Solubility ing figures have been provided by way of explanation and No. Compound (mg/mL) pH illustration, and are not intended to limit the scope of the Saha O.1 7.95 appended claims. Many variations in the presently preferred Na(saha) O.69 10 embodiments illustrated herein will be apparent to one of 1 Mg(saha) O41 7.94 ordinary skill in the art, and remain within the scope of the appended claims and their equivalents. US 2014/0274936 A1 Sep. 18, 2014 1. A metal coordination complex of a biologically active 12. A method for treating emesis, comprising: administer moiety and a metal, wherein the biologically active moiety is ing the complex of claim 7 to a patient in need of the biologi selected from the group consisting of mycophenolate, fin cally active agent. golimod, baclofen, acamprosate, tiXocortol, pregabalin, 13. A method for treating epilepsy comprising: adminis 7-phenyl-2,4,6-hepta-trienal hydroxamic acid, (S)-(+)-a- tering the complex of claim 7 to a patient in need of the amino-4-carboxy-2-methylbenzeneacetic acid, eglumegad, biologically active agent. (2S,2R,3R)-2-(2',3'-dicarboxycyclo-propyl)glycine, rema 14. A method for treating coeliac disease, comprising: cemide, azathioprine, Zonisamide, balsalazide, dobutamine, administering the complex of claim 7 to a patient in need of epinephrine, ganciclovir, 6-MP modafinil, norepinephrine, the biologically active agent. ribavirin, Zoledronic acid, and their derivatives. 15. A method for treating Alzheimer's disease, comprising: 2. The complex of claim 1, wherein the metal is selected administering the complex of claim 7 to a patient in need of from: S-block metals, d-block metals, and p-block metals. 3. A pharmaceutical composition comprising a complex of the biologically active agent. claim 1 and a pharmaceutically acceptable excipient. 16. A method for treating multiple Sclerosis, comprising: 4. A pharmaceutical composition comprising a complex of administering the complex of claim 7 to a patient in need of claim 2 and a pharmaceutically acceptable excipient. the biologically active agent. 5. A method of treating an indication, comprising admin 17. A method for treating emesis, comprising: administer istering the complex of claim 1 to a patient in need of the ing the composition of claim 11 to a patient in need of the biologically active agent for the indication. biologically active agent. 6. A method of treating an indication, comprising admin 18. A method for treating epilepsy comprising: adminis istering the pharmaceutical composition of claim 3 to a tering the composition of claim 11 to a patient in need of the patient in need of the biologically active agent for the indica biologically active agent. tion. 19. A method for treating coeliac disease, comprising: 7. A coordination complex comprising a metal and a bio administering the composition of claim 11 to a patient in need logically active agent which is a cannabinoid. of the biologically active agent. 8. The complex of claim 7, wherein the biologically active 20. A method for treating Alzheimer's disease, comprising: agent is an antiemetic agent. administering the composition of claim 11 to a patient in need 9. The complex of claim 7, wherein the biologically active agent is an antiepileptic agent. of the biologically active agent. 10. The complex of claim 7, wherein the metal is selected 21. A method for treating multiple sclerosis, comprising: from: S-block metals, d-block metals, and p-block metals administering the composition of claim 11 to a patient in need 11. A pharmaceutical composition comprising a complex of the biologically active agent. of claim 7 and a pharmaceutically acceptable excipient. k k k k k