Title:  N,N-dinitramide salts as solubilizing agents for biologically active agents

United States Patent:  6,833,478

Issued:  December 21, 2004

Inventors:  Bottaro; Jeffrey C. (Mountain View, CA); Petrie; Mark A. (Cupertino, CA); Penwell; Paul E. (Menlo Park, CA); Bomberger; David C. (Belmont, CA)

Assignee:  SRI International (Menlo Park, CA)

Appl. No.:  905577

Filed:  July 13, 2001

Abstract

A method is provided for enhancing the solubility of an ionizable compound in a lipophilic medium by admixing the compound with an effective solubility-enhancing amount of an N,N-dinitramide salt. The ionizable compound, upon ionization, gives rise to a biologically active cationic species that ionically associates with the N,N-dinitramide anion N(NO_{2)2^- fo}llowing admixture with the N,N-dinitramide salt. The biologically active cationic species may be a pharmacologically active cation, in which case the method is useful for enhancing the penetration of the blood-brain barrier by the pharmacologically active cation. In other embodiments, the ionizable compounds are medical imaging or diagnostic agents, or agricultural agents such as pesticides. Salts of biologically active cations and N,N-dinitramide ion are also provided as novel compositions of matter.

SUMMARY OF THE INVENTION

Accordingly, in one embodiment, the invention provides a method for enhancing the solubility of an ionizable compound in a lipophilic medium by admixing the ionizable compound with an effective solubility enhancing amount of an N,N-dinitramide salt. The ionizable compound may be in either ionized or un-ionized form prior to admixture, and if in ionized form, in association with an anionic counterion. The ionizable compound, upon ionization, gives rise to a biologically active cationic species that becomes ionically associated with the N,N-dinitramide anion following admixture. The biologically active cationic species may be a pharmacologically active cation.

Preferred ionizable compounds are ionizable pharmacologically active agents, e.g., those which are centrally acting agents such as CNS amines or other nervous system agents, such as: sympathomimetic amines; neuroprotective and neuroregenerative agents, including neurotrophic factors; neuroactive amino acids and peptides; neurotransmitters; agents to treat neurodegenerative disorders; CNS and respiratory stimulants; and drugs that selectively modify CNS function. The ionizable pharmacologically active agent may also be a metal-based drug or a dietary supplement such as a vitamin, a mineral, or another nutritional supplement.

The ionizable compounds may also be medical imaging or diagnostic agents, or an agricultural chemical agent such as a pesticide.

In a related embodiment, the invention provides novel salts formed by reaction of the ionizable compounds with an N,N-dinitramide salt, wherein the salts comprise the biologically active cation of the ionizable compound is in association with N,N-dinitramide anion. The salts have significantly enhanced solubility in lipophilic media relative to that of the ionizable compound.

In a further embodiment, methods of use are provided. One such method is a process for enhancing the penetration of the blood-brain barrier by a pharmacologically active agent, wherein the method involves coadministering the active agent with an N,N-dinitramide salt or coadministering the active agent as an N,N-dinitramide salt.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The N,N-Dinitramide Salt

The N,N-dinitramide salts useful as solubilizers herein have the formula M^+x[N(NO₂)₂^-]_x wherein M is selected so that it is displaced by the biologically active cationic species upon admixture and/or co-administration of the N,N-dinitramide salt with the ionizable compound, and x is the cationic charge of M. M is a cation selected from the group consisting of a metal ion, an inorganic nitrogen-containing cation, and a cationic derivative of an organic compound having one or more tetravalent nitrogen atoms.

Metallic cations: Suitable metals for the M moiety include the alkali metals Li, Na, K, Rb, and Cs of Group 1 of the Periodic Table of the Elements; the Group 2 alkaline earth metals Ca, Ba, Sr, and Mg; the Group 11 metals Cu, Ag, and Au; the Group 12 metals Zn, Cd, and Hg; the Group 3 metals Al, Sc, Y, Ga, In, and the lanthanides (57-71); the Group 4 metals Ti, Zr, Hf, Ge, and Sn; Group 5 metals V, Nb, and Ta; the Group 6 metals Cr, Mo, and W; the Group 7 metals Mn, Tc, and Re; the Group 8 metals Fe, Ru and Os; and the Group 9 metals Co, Rh and Ir; the Group 10 metals Ni, Pd and Pt. Of the foregoing, Li, Na, K, Be, and Mg are preferred. All references to group numbers in the Periodic Table of the Elements are to the new IUPAC format for numbering elements and groups, as set forth in the CRC Handbook of Chemistry and Physics, 81^st Edition, Lide, Ed., 2001.

As noted above, M may also be an inorganic nitrogen-containing cation, including, but not necessarily limited to, the ammonium (NH--₄⁺), hydrazinium (H₂ N--NH₃⁺), nitronium (O=N=)⁺), and nitrosonium (N=O⁺) cations, although the ammonium ion is preferred (in which case the N,N-dinitramide salt is referred to as ammonium dinitramide).

Some cationic derivatives of organic compounds having one or more tetravalent nitrogen atoms and have the formula R_k H_m N_n^+q, wherein:

n is an integer in the range of 1 to 8;

k is an integer in the range of 1 to 2+n;

q is an integer in the range of 1 to n;

m is equal to n+2+q-k; and

each R is C₁- C₁₂ hydrocarbyl, typically linear or branched lower alkyl.

Preferred nitrogen-containing cations within the aforementioned group contain 1 or 2 nitrogen atoms. Specific examples of such ions include, but are not limited to, CH₃ NH₃⁺, (CH₃)₂ NH₂⁺, (CH₃)₃ NH⁺, (CH₃)₄ N⁺, C₂ H₅ NH₃⁺, (C₂ H₅)₂ NH₂⁺, (C₂ H₅)₃ NH⁺, C₂ H₅)₄ N⁺, (C₂ H₅)(CH₃)NH₂⁺, (C₂ H₅)(CH₃) ₂ NH⁺, (C₂ H₅)₂ (CH₃)₂ N⁺, (C₃ H₇)₄ N⁺, (C₄ H₉)₄ N⁺, CH₃ N₂ H₄⁺, (CH₃)₂ N₂ H₃⁺, (CH₃) ₂ N₂ H₃⁺, (CH₃)₃ N₂ H₂⁺, (CH₃)₄ N₂ H⁺, and (CH₃)₅ N₂⁺.

Other cationic derivatives of organic compounds that can serve as M⁺ include guanidinium (a cationic derivative of guanidine), biguanidinium (a cationic derivative of biguanidine), the guanylurea cation H₂ N(NH)CNH₂ C(O)NH₂)⁺, ethylenediaminium (a cationic derivative of ethylenediamine), piperazinediium (a cationic derivative of piperazine), monoaminoguanidinium (a cationic derivative of monoaminoguanidine), diaminoguanidinium (a cationic derivative of diaminoguanidine), triaminoguanidinium (a cationic derivative of triaminoguanidine), tetrazolium (a cationic derivative of tetrazole), aminotetrazolium (a cationic derivative of aminotetrazole), amino-ammonium-furazan (a cationic derivative of diaminofurazan), polyvinylammonium (a cationic derivative of polyvinylammonia), and dicyandiamidium (a cationic derivative of dicyandiamide). See, for example, U.S. Pat. Nos. 5,254,324 to Bottaro et al. and 6,117,255 to Blomquist.

Ammonium dinitramide, or "ADN," is a particularly preferred solubilizing agent. ADN has the chemical formula NH₄⁺ (N(NO₂)₂^-), and can be obtained from SRI International in Menlo Park, Calif. ADN may also be readily prepared, using the methods disclosed in the art. See, for example, U.S. Pat. Nos. 5,198,204 and 5,254,324 to Bottaro et al. and 5,316,749 and 5,415,852 to Schmitt et al., all assigned to SRI International.

III. The Biologically Active Agent

The ionizable compound herein is a biologically active agent that upon ionization gives rise to a biologically active cationic species in association with an anionic counterion. The ionizable compound that is admixed with the N,N-dinitramide salt will, accordingly, be a biologically active agent in one the following forms:

(1) a salt comprised of a biologically active cationic species (generally a nitrogen-containing cationic species that includes at least one positively charged nitrogen atom) and an anionic counterion; or

(2) an electronically neutral compound that:

(a) ionizes upon admixture with the N,N-dinitramide salt to give a biologically active cationic species in ionic association with the N,N-dinitramide anion; and/or

(b) becomes protonated in an aqueous medium at physiological pH to give a biologically active cationic species in ionic association with one or more hydroxide counterions.

The biologically active agent may be a pharmacologically active agent or any other compound that has a biological, chemical and/or physical effect on a biological system, i.e., on a living organism. Biologically active agents herein include, by way of example, pharmacologically active agents (e.g., prophylactic and therapeutic pharmaceutical agents), medical imaging and diagnostic agents, dietary supplements, and agricultural chemicals.

One group of biologically active agents of interest herein are cationic species having the formula NR₄⁺, in association with a negatively charged anion. The R groups may be the same or different, and are independently selected from C_1-30 hydrocarbyl groups, substituted C_1-30 hydrocarbyl groups, heteroatom-containing C_1-30 hydrocarbyl groups, and substituted heteroatom-containing C_1-30 hydrocarbyl groups, e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, alkaryl, heteroaryl, and the like.

A. Pharmacologically Active Agents

In one embodiment, then, the biologically active agent is a pharmacologically active agent, generally a hydrophobic active agent. Preferred pharmacologically active agents are centrally acting drugs, particularly CNS active agents and other nervous system agents, including, but not limited to, the following: sympathomimetic amines; neuroprotective and neuroregenerative agents, including neurotrophic factors; neuroactive amino acids and peptides; neurotransmitters; muscarinic receptor agonists and antagonists; anticholinesterases; neuromuscular blocking agents; ganglionic stimulating drugs; agents to treat neurodegenerative disorders such as Alzheimer's disease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS); anti-epileptic agents; CNS and respiratory stimulants; and drugs that selectively modify CNS function, including anesthetic agents, analgesic agents, antiemetic agents, antihypertensive agents, cerebral vasodilators, hypnotic agents and sedatives, anxiolytics and tranquilizers, neuroleptic agents, anti-microbial agents, alpha adrenergic receptor antagonists, and appetite suppressants. Some agents, as will be appreciated by those of ordinary skill in the art, are encompassed by two or more of the aforementioned groups.

Examples of these pharmacologically active agents are as follows:

Sympathomimetic amines. Sympathomimetic amines, including the catecholamines, are amine drugs that mimic the actions of drugs that activate the sympathetic nervous system, such as epinephrine and norepinephrine. Sympathomimetic amines thus include albuterol, amphetamine, benzphetamine, colterol, diethylpropion, dopamine, dopamine hydrochloride, dobutamine, ephedrine, epinephrine, epinephrine bitartrate, ethylnorepinephrine, ethylnorepinephrine hydrochloride, fenfluramine, fenoldapam, fenoldopam, fenoldopam mesylate, hydroxyamphetamine, hydroxyamphetamine hydrobromide, ibopamine, isoetharine, isoproterenol, isoproterenol hydrochloride, mephentermine, mephentermine sulfate, metaproterenol, metaraminol, metaraminol bitartrate, methoxamine, methoxamine hydrochloride, midodrine, norepinephrine, norepinephrine bitartrate, phendimetrazine, phenmetrazine, phentermine, phenylephrine, phenylephrine hydrochloride, phenylethylamine, phenylpropanolamine, prenalterol, propylhexedrine, ritodrine, terbutaline, terbutaline sulfate, and tyramine.

Neuroprotective and neuroregenerative agents. These include excitatory amino acid antagonists and neurotrophic factors, e.g., brain derived neurotrophic factor, ciliary neurotrophic factor, and nerve growth factor, neurotrophin(NT) 3 (NT3), NT4 and NT5.

Neuroactive amino acids andpeptides. The primary neuroactive amino acids are .gamma.-aminobutyric acid (GABA), glycine, .beta.-alanine, taurine, and glutamate, and the neuroactive peptides include bradykinin, kallidin, des-Arg⁹ -bradykinin, des-Arg¹⁰ -kallidin, des-Arg⁹ -[Leu⁸ ]-bradykinin, [D-Phe⁷ ]-bradykinin, HOE 140, neuropeptide Y, enkaphalins and related opioid peptides such as Met⁵ -enkaphalin, Leu⁵ -enkephalin, .alpha.-, .beta.-and .gamma.-endorphin, .alpha.-and .beta.-neo-endorphin, and dynorphin.

Neurotransmitters. The primary neurotransmitters, as will be appreciated by those of ordinary skill in the art, are GABA (.gamma.-aminobutyric acid), glycine, glutamate, acetylcholine, dopamine, epinephrine, 5-hydroxytryptamine, substance P, serotonin, enkaphalins and related opioid peptides as above, and catecholamines.

Muscarinic receptor agonists and antagonists. Muscarinic receptor agonists include, by way of example: choline esters such as acetylcholine, methacholine, carbachol, bethanechol (carbamylmethylcholine), bethanechol chloride; cholinomimetic natural alkaloids and synthetic analogs thereof, including arecoline, pilocarpine, muscarine, McN-A-343, and oxotremorine. Muscarinic receptor antagonists are generally belladonna alkaloids or semisynthetic or synthetic analogs thereof, such as atropine, scopolamine, homatropine, homatropine methylbromide, ipratropium, methantheline, methscopolamine and tiotropium.

Anticholinesterases. As is well known, the function of acetylcholinesterase (AChE) is to terminate the action of acetylcholine at the junctions of various cholinergic nerve endings with their effector organs or postsynaptic sites. See, for example, Goodman Gilman's The Pharmacological Basis of Therapeutics, 9^th Edition, Jardman et al, Eds. (1996), at Chapter 8. Anticholinesterase agents inhibit the action of ACHE and thus results in the accumulation of acetylcholine at cholinergic receptor cites, stimulating cholinergic receptors throughout the CNS and peripheral nervous system (PNS). Anticholinesterases include, for example, ambenonium, ambenonium chloride, demecarium, demecarium bromide, echothiophate iodide, edrophonium, edrophonium chloride, neostigmine, neostigmine bromide, neostigmine methylsulfate, physostigmine, physostigmine salicylate, pyridostigmine, and pyridostigmine bromide.

Neuromuscular blocking agents and ganglionic blocking drugs. Neuromuscular blocking agents include dicholine esters (e.g., succinylcholine), benzylisoquinolines (d-tubocurarine, atracurium, doxacurium, mivacurium) and pipecuronium, rocuronium, vecuronium), while the primary ganglionic stimulating drugs are hexamethonium, trimethaphan, and mecamylamine.

Agents to treat neurodegenerative diseases. Active agents for treating Alzheimer's disease and Huntington's disease are drugs useful for treating dementias and/or enhancing memory and learning processes. Donezepil, donepezil hydrochloride, physostigmine, physostigmine salicylate, tacrine and tacrine hydrochloride are active agents typically used for treatment of Alzheimer's Disease, while fluoxetine and carbamazepine are used to treat Huntington's Disease. Anti-Parkinsonism drugs useful herein include amantadine, apomorphine, bromocriptine, levodopa (particularly a levodopa/carbidopa combination), pergolide, ropinirole, selegiline, trihexyphenidyl, trihexyphenidyl hydrochloride, and anticholinergic agents. ALS is generally treated with spasmolytic (anti-spastic) agents such as baclofen, diazepam, tizanidine, and dantrolene.

Anti-epileptic agents. Suitable anti-epileptic agents are anti-convulsant (anti-seizure) drugs such as azetazolamide, carbamazepine, clonazepam, clorazepate, ethosuximide, ethotoin, felbamate, gabapentin, lamotrigine, mephenytoin, mephobarbital, phenytoin, phenobarbital, primidone, trimethadione, vigabatrin and the benzodiazepines. Benzodiazepines, as is well known, are useful for a number of indications, including anxiety, insomnia, and nausea.

CNS and respiratory stimulants. CNS and respiratory stimulants also encompass a number of active agents useful herein. These stimulants include, but are not limited to, the following: xanthines such as caffeine and theophylline; amphetamines such as amphetamine, benzphetamine hydrochloride, dextroamphetamine, dextroamphetamine sulfate, levamphetamine, levamphetamine hydrochloride, methamphetamine, and methamphetamine hydrochloride; and miscellaneous stimulants such as methylphenidate, methylphenidate hydrochloride, modafinil, pemoline, sibutramine, and sibutramine hydrochloride.

Drugs that selectively modify CNSfunction. These include, without limitation:

(1) anesthetic agents such as ketamine;

(2) opioid analgesics such as alfentanil, buprenorphine, butorphanol, codeine, drocode, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, sufentanil, and tramadol;

(3) nonopioid analgesics such as apazone, etodolac, diphenpyramide, indomethacine, meclofenamate, mefenamic acid, oxaprozin, phenylbutazone, piroxicam, and tolmetin;

(4) antiemetics such as chlorpromazine, cisapride, domperidone, granisetron, metoclopramide, ondansetron, perphenazine, prochlorperazine, promethazine, thiethylperazine, and triflupromazine;

(5) antihypertensive agents such as apraclonidine, clonidine, guanfacine, and guanabenz;

(6) cerebral vasodilators such as vincamine, naftidrofuryl oxalate, papaverine, and nicotinic acid;

(7) hypnotic agents and sedatives such as clomethiazole, ethinamate, etomidate, glutethimide, meprobamate, methyprylon, zolpidem, and barbiturates (e.g., amobarbital, apropbarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, thiopental);

(8) anxiolytics and tranquilizers such as benzodiazepines (e.g., alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam, triazolam), buspirone, and droperidol;

(9) neuroleptic agents, including antidepressant drugs, antimanic drugs, and antipsychotic agents, wherein

antidepressant drugs include (a) the tricyclic antidepressants such as amoxapine, amitriptyline, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortryptiline, protryptiline, and trimipramine, (b) the serotonin reuptake inhibitors citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine, (c) monoamine oxidase inhibitors such as phenelzine, tranylcypromine, and (-)-selegiline, and (d) other, "atypical" antidepressants such as bupropion, nefazodone, and trazodone venlafaxine, and

antimanic and antipsychotic agents include (a) phenothiazines such as acetophenazine, acetophenazine maleate, chlorpromazine, chlorpromazine hydrochloride, fluphenazine, fluphenazine hydrochloride, fluphenazine enanthate, fluphenazine decanoate, mesoridazine, mesoridazine besylate, perphenazine, thioridazine, thioridazine hydrochloride, trifluoperazine, and trifluoperazine hydrochloride, (b) thioxanthenes such as chlorprothixene, thiothixene, and thiothixene hydrochloride, and (c) other heterocyclic drugs such as carbamazepine, clozapine, droperidol, haloperidol, haloperidol decanoate, loxapine succinate, molindone, molindone hydrochloride, olanzapine, pimozide, quetiapine, risperidone, and sertindole;

(10) anticholinergic drugs such as atropine, scopolamine and glycopyrrolate;

(11) anti-microbial agents such as

(a) tetracycline antibiotics and related compounds (chlortetracycline, oxytetracycline, demeclocycline, methacycline, doxycycline, rolitetracycline),

(b) macrolide antibiotics such as erythromycin, clarithromycin, and azithromycin,

(c) streptogramin antibiotics such as quinupristin and dalfopristin,

(d) beta-lactam antibiotics, including penicillins (e.g., penicillin G, penicillin VK), antistaphylococcal penicillins (e.g., cloxacillin, dicloxacillin, nafcillin, and oxacillin), extended spectrum penicillins (e.g., aminopenicillins such as ampicillin and amoxicillin, and the antipseudomonal penicillins such as carbenicillin), and cephalosporins (e.g., cefadroxil, cefepime, cephalexin, cefazolin, cefoxitin, cefotetan, cefuroxime, cefotaxime, ceftazidime, and ceftriazone), and carbapenems such as imiprenem, meropenem and aztreonam,

(e) aminoglycoside antibiotics such as streptomycin, gentamicin, tobramycin, amikacin, and neomycin,

(f) glycopeptide antibiotics such as vancomycin, and teicoplanin;

(g) sulfonamide antibiotics such as sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole, and sulfamethoxazole,

(h) quinolone antibiotics such as ciprofloxacin, nalidixic acid, and ofloxacin;

(i) anti-mycobacterials such as isoniazid, rifampin, rifabutin, ethambutol, pyrazinamide, ethionamide, aminosalicylic, and cycloserine,

(j) systemic antifungal agents such as itraconazole, ketoconazole, fluconazole, and amphotericin B,

(k) antiviral agents such as acyclovir, famcicylovir, ganciclovir, idoxuridine, sorivudine, trifluridine, valacyclovir, vidarabine, didanosine, stavudine, zalcitabine, zidovudine, amantadine, interferon alpha, ribavirin and rimantadine, and

(l) miscellaneous antimicrobial agents such as chloramphenicol, spectinomycin, polymyxin B (colistin), and bacitracin;

(12) alpha adrenergic receptor antagonists such as doxazosin, indoramine, phenoxybenzamine, phentolamine, prazosin, tolazoline, terazosin, trimazosin, and yohimbine; and

(13) appetite suppressants such as amphetamine, dextroamphetamine, dextroamphetamine sulfate, diethylpropion hydrochloride, mazindol, methamphetamine hydrochloride, phentermine, and phentennine hydrochloride.

For certain active agents that are commercially available in the form of an acid addition salt, the commercially available salt form is indicated above along with the free base form of the drug. However, any of the foregoing active agents may be in the form of either the free base (i.e., as an un-ionized, electronically neutral compound) or as any pharmaceutically acceptable acid addition salt thereof, formed with either an inorganic or an organic acid. Suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, while suitable organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

The methodology of the invention may also be used with pharmacologically active agents other than the aforementioned "centrally active agents," and include other nitrogenous drugs as well as metal-based drugs, discussed infra, and nutritional supplements, including vitamins, minerals and other dietary supplements.

The term "vitamin" is used in the conventional sense to refer to trace organic substances that are required in the diet, and includes without limitation, thiamin, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, vitamin B₁₂, vitamin A, vitamin D, vitamin E and vitamin K. Also included within the term "vitamin" are the coenzymes thereof, such as thiamine pyrophosphates (TPP), flavin mononucleotide (FMM), flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide (NAD), nicotinamide adenine dinucleotide phosphate (NADP), Coenzyme A (CoA), Coenzyme Q (CoQ), pyridoxal phosphate, biocytin, tetrahydrofolic acid, and coenzyme B₁₂. The term "vitamin" also includes choline and carnitine. The term "mineral" refers to inorganic substances that are required in the human diet, and includes, without limitation, calcium, magnesium, iron, zinc, selenium, copper, manganese, chromium, molybdenum, etc. The term "dietary supplement" as used herein means a substance that has an appreciable nutritional effect when administered in small amounts.

B. Metal-Containing Biologically Active Agents

Metal-based drugs, as alluded to in the aforementioned section, represent an additional class of compounds with which the present invention is useful. The drug may be any metal-containing drug in which the metal atom, when charged and thus in cationic form, is biologically active. Such drugs include, by way of example: anticancer agents, containing Al, Ga, In, Ti, Ru, Pt, Au, or Sn (a specific example is cisplatin); antimicrobial agents, containing Cu, Zn, Ag, Hg, or Bi (such as silver sulfadiazine); antiarthritic agents, containing Au (such as aurothioglucose, aurothiomalate, and auranofin), antipsychotic agents, such as lithium; antihypertensive agents, containing Fe or Zn; antiviral agents containing, e.g., Li, Pt, Au, W, or Cu; antiulcer drugs containing bismuth; antacid agents containing, e.g., Al, Na, Mg or Ca; radiosensitizing agents for cancer therapy, containing, e.g., Pt or Ru; metalloporphyrins and metallochlorins for photodynamic therapy; insulin mimetics containing, e.g., Cr or V; mineral supplements such as Ca, Mg, Fe, Zn, Se, Cu, Mn, Cr, Mo, K; contrast agents for magnetic resonance imaging containing, e.g., Mn, Gd, Fe; X-ray imaging agents, such as Ba-containing compounds; diagnostic radio-imaging agents, e.g. ^99m Tc, ¹¹¹ In; .beta.-emitters useful for therapy (e.g., ⁹⁰ Y, ²¹² Bi);metalloenzyme mimetics (Mn, Cu, Fe); and radiotherapy agents (e.g. Re, Y, Pb).

C. Agricultural Chemicals

Other suitable biologically active agents with which the present invention may be advantageously employed are agricultural chemicals, e.g., compounds that can be used as agricultural fertilizers, nutrients, plant growth accelerants, plant growth controlling chemicals, insect growth regulators, and pesticides, with the term "pesticides" including, but not limited to, acaricides, avicides, bacteriocides, fungicides, insecticides, larvicides, miticides, molluscicides, nematocides, ovicides, predicides, pupicides, and rodenticides. Common pesticides that are ionizable to give a biologically active cation, and may thus benefit from the method and formulations of the invention, include acylalanines, haloacetanilides, triazole derivatives, pyrethroids, formamidines, and strobilurines.

Examples of specific, representative agricultural chemicals with which the methodology of the invention may be advantageously employed include, but are not limited to, the following:

Atrazine (2-chloro-4-ethylamino-6 isopropylamino-s-triazine);

Simazine (2-chloro-4,6,-bis-(ethylamino)-s-triazine);

Dodine (n-dodecylguanidine acetate);

Thiram (tetramethylthiuram disulfide);

Manazon (s-(4,6-diamino-1,3,5-triazin-2-yl methyl)dimethyl phosphorothiolthionate);

PP 675 (5-butyl-2-dimethylamino-4-hydroxy-6-methyl pyrimidine);

PP 062 (5,6-dimethyl-2-dimethylamino-4 pyrimidinyl dimethylcarbamate);

PP 149 (5-n-butyl-2 ethylamino-4-hydroxy-6 methylpyrimidine);

GS 14260 (4-ethylamino-2-methylthio-6-t-butyl-amino-1,3,5-triazine);

Pyrazon (5-amino-4-chloro-2-phenyl-3-pylidazone);

WL 9385 (2-Azido-4-ethylamino-6-t-butylamino-s-triazine);

Ametryne (2-methylmercapto-4-ethylamino-6-isopropyl-amino-s-triazine);

Prometryne(2-methylmercapto-4,6-bisisopropyl amino-s-triazine);

Benefin (N-butyl-N-ethyl-2,2,2-trifluoro-2,6-dinitro-p-toluidine); and

Nitralin (2,6-dinitro-4-methylsulfonyl-N,N-dipropyl-aniline).

IV. Pharmaceutical Compositions, Dosage Forms and Modes of Administration

Pharmaceutical compositions and dosage forms may contain (1) an N,N-dinitramide salt of a biologically active agent as described in Sections IIIA and IIIB, or (2) an N,N-dinitramide anion and the biologically active agent (wherein the active agent may be either electronically neutral or in the form of a salt). Alternatively, the biologically active agent and the N,N-dinitramide salt may be in separate dosage forms. In the latter case, the active agent and the N,N-dinitramide salt may or may not be administered at the same time. In some cases, it may be advantageous for delivery of drugs across the blood-brain barrier for the N,N-dinitramide salt to be administered on the order of 30 minutes to 2 hours before administration of the active agent.

In any of the aforementioned embodiments, the amount of the N,N-dinitramide salt that is co-administered with the biologically active agent should be an effective solubility enhancing amount, i.e., an amount effective to increase the solubility of the biologically active agent in a lipophilic medium and thereby enhance bioavailability and transport across lipophilic membranes and the blood-brain barrier. The effective solubility enhancing amount of the N,N-dinitramide salt is generally selected to provide a molar ratio of the N,N-dinitramide salt to the ionizable compound (i.e., the biologically active agent, whether in ionized or unionized form) in the range of about 0.5z:1 to about 5z:1 wherein z is the charge of the biologically active cationic species. Preferably, the amount is selected to provide a molar ratio of the N,N-dinitramide salt to the active agent in the range of about 1z:1 to about 2z:1, and most preferably about 1z: 1 to about 1.5z: 1. Of course, if the active agent is administered in the form of an N,N-dinitramide salt, such that a biologically active cationic species is associated with the dinitramide anion, the ratio of the dinitramide anion to the biologically active cationic species will be approximately 1z:1 wherein, again, z is the charge of the biologically active cationic species.

The compounds may be administered orally, parenterally, rectally, vaginally, buccally, sublingually, nasally, by inhalation, topically, transdermally, or via an implanted reservoir in dosage forms containing conventional non-toxic pharmaceutically acceptable carriers and excipients. The term "parenteral" as used herein is intended to include subcutaneous, intravenous, and intramuscular injection. The amount of biologically active agent administered will, of course, be dependent on the particular active agent, the condition or disorder being treated, the severity of the condition or disorder, the subject's weight, the mode of administration and other pertinent factors known to the prescribing physician.

Depending on the intended mode of administration, the pharmaceutical compositions may be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, capsules, caplets, liquids, suspensions, emulsions, suppositories, granules, pellets, beads, powders, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.

Oral dosage forms are preferred, and include tablets, capsules, caplets, and nonaqueous solutions, suspensions and or syrups, and may also comprise a plurality of granules, beads, powders or pellets that may or may not be encapsulated. Such dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and are described in the pertinent texts, e.g., in Remington: The Science and Practice of Pharmacy, 20^th Edition, Gennaro, A. R., Ed. (Lippincott, Williams and Wilkins, 2000).

Tablets are the preferred oral dosage forms, and may be manufactured using standard tablet processing procedures and equipment. One method for forming tablets herein is by direct compression of a powdered, crystalline or granular composition containing the N,N-dinitramide salt, the biologically active agent, or both, alone or in combination with diluents, binders, lubricants, disintegrants, colorants or the like. As an alternative to direct compression, tablets can be prepared using wet-granulation or dry-granulation processes. Tablets may also be molded rather than compressed, starting with a moist or otherwise tractable material; however, compression and granulation techniques are preferred.

In addition to the N,N-dinitramide salt of the biologically active agent (or, in an alternative embodiment, as discussed above, the N,N-dinitramide salt and/or the biologically active agent,), the tablet will generally contain other materials such as binders, diluents, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like. An additional active agent may also be included if desired. Binders are used to impart cohesive qualities to the tablet core, and thus ensure that the core remains intact after compression and prior to coating. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum. Diluents are typically necessary to increase bulk so that a practical size tablet is ultimately provided. Suitable diluents include dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Lubricants are used to facilitate manufacture of the drug-containing core; examples of suitable lubricants include, for example, magnesium stearate, calcium stearate, and stearic acid. Stearates, if present, preferably represent at no more than approximately 2 wt. % of the drug-containing core. Disintegrants are used to facilitate disintegration of the tablet, and are generally starches, clays, celluloses, algins, gums or crosslinked polymers. Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride and sorbitol. Stabilizers are used to inhibit or retard drug decomposition reactions that include, by way of example, oxidative reactions. Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents.

The dosage form may also be a capsule, in which case the active agent-containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets). Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, Nineteenth Edition. (1995) cited supra, which describes materials and methods for preparing encapsulated pharmaceuticals. If the active-agent containing composition is present within the capsule in liquid form, a lipophilic carrier is necessary to dissolve the biologically active agent and/or the N,N-dinitramide salt. The lipophilic carrier must be compatible with all components of the composition, and must be suitable for ingestion.

Suitable lipophilic carriers include, but are not limited to, the following: phospholipids such as phosphorylated diacyl glycerides, and particularly phospholipids selected from the group consisting of diacyl phosphatidylcholines, diacyl phosphatidylethanolamines, diacyl phosphatidylserines, diacyl phosphatidylinositols, diacyl phosphatidylglycerols, diacyl phosphatidic acids, and mixtures thereof; fatty acids such as isovaleric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, oleic acid, linoleic acid, linolenic acid, and arachidonic acid; lower fatty acid esters comprising esters of the foregoing fatty acids, wherein the carboxylic acid group of the fatty acid is replaced with an ester moiety --(CO)--OR wherein R is a C₁ -C₃ alkyl moiety optionally substituted with one or two hydroxyl groups; fatty alcohols corresponding to the aforementioned fatty acids, wherein the carboxylic acid group of the fatty acid is replaced by a --CH₂ OH group; glycolipids such as cerebroside and gangliosides; and oils, including animal oils such as cod liver oil and, menhaden oil, and vegetable oils such as babassu oil, castor oil, corn oil, cotton seed oil, linseed oil, mustard oil, olive oil, palm oil, palm kernel oil, peanut oil, poppyseed oil, rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower seed oil, tung oil or wheat germ oil.

Solid dosage forms, whether tablets, capsules, caplets, or particulates, may, if desired, be coated so as to provide for delayed release. For example, enteric coatings may be necessary if it is desired to prevent drug release in the upper gastrointestinal tract. Enterically coated dosage forms of the invention may be manufactured using standard coating procedures and equipment. Such procedures are known to those skilled in the art and described in the pertinent texts, e.g., in Remington, supra. Generally, after preparation of the solid dosage form, an enteric coating composition is applied using a coating pan, an airless spray technique, fluidized bed coating equipment, or the like. Enteric coating compositions comprise a polymeric material that prevents drug release in the acidic environment of the stomach but dissolve sufficiently in the small intestines to gradually release the active agent therein. Suitable enteric polymers include, but are not limited to, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulose succinate, carboxymethyl ethylcellulose, hydroxypropyl methylcellulose acetate succinate, shellac, zein, and acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate.

Sustained release dosage forms provide for drug release over an extended time period, and may or may not be delayed release. Generally, as will be appreciated by those of ordinary skill in the art, sustained release dosage forms are formulated by dispersing a drug within a matrix of a gradually bioerodible (hydrolyzable) material such as an insoluble plastic, a hydrophilic polymer, or a fatty compound, or by coating a solid, drug-containing dosage form with such a material. Insoluble plastic matrices may be comprised of, for example, polyvinyl chloride or polyethylene. Hydrophilic polymers useful for providing a sustained release coating or matrix cellulosic polymers include, without limitation: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylcellulose phthalate, cellulose hexahydrophthalate, cellulose acetate hexahydrophthalate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g. copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, with a terpolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride (sold under the tradename Eudragit RS) preferred; vinyl polymers and copolymers such as polyvinyl pyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene-vinyl acetate copolymers; zein; and shellac, ammoniated shellac, shellac-acetyl alcohol, and shellac n-butyl stearate. Fatty compounds for use as a sustained release matrix material include, but are not limited to, waxes generally (e.g., carnauba wax) and glyceryl tristearate.

Preparations according to this invention for parenteral administration include are sterile nonaqueous solutions, suspensions, or emulsions. Examples of nonaqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using a sterile injectable medium.

Although the present compositions will generally be administered orally or parenterally, preferably using a solid oral dosage form, other modes of administration are suitable as well. For example, administration may be rectal or vaginal, preferably using a suppository that contains, in addition to the active agent and/or the N,N-dinitramide salt, excipients such cocoa butter or a suppository wax. Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art. The pharmaceutical compositions of the invention may additionally be administered by inhalation. Such compositions may be formulated according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents. Preferred formulations for inhalation are particulate formulations administered using a dry powder inhaler, and aerosol formulations containing a suitable propellant and administered using a pressurized metered dose inhaler.

Topical and transdermal administration are also suitable delivery routes in conjunction with the methodology of the invention. Topical formulations may be in any form suitable for application to the body surface, and may comprise, for example, an ointment, cream, gel, lotion, solution, paste or the like, and/or may be prepared so as to contain liposomes, micelles, and/or microspheres. Ointments, as is well known in the art of pharmaceutical formulation, are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery, and, preferably, will provide for other desired characteristics as well, e.g., emolliency or the like. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing. Creams, as also well known in the art, are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. Various additives, known to those skilled in the art, may be included in the topical formulations. For example, solubilizers may be used to solubilize certain active agents. For those drugs having an unusually low rate of permeation through the skin or mucosal tissue, it may be desirable to include a permeation enhancer in the formulation.

The invention may also be used in conjunction with administration through the skin or mucosal tissue using conventional transdermal drug delivery systems, wherein the system is comprised of a laminated structure (typically referred to as a transdermal "patch") that serves as a drug delivery device to be affixed to the skin. Transdermal drug delivery may involve passive diffusion or it may be facilitated using electrotransport, e.g., iontophoresis. In a typical transdermal "patch," the drug composition is contained in a layer, or "reservoir," underlying an upper backing layer. The laminated structure may contain a single reservoir, or it may contain multiple reservoirs. In one type of patch, referred to as a "monolithic" system, the reservoir is comprised of a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.

The invention accordingly provides a novel and highly effective means for increasing the solubility of a hydrophobic, cationic compound in a lipophilic medium, and for enhancing the transport of a hydrophobic, cationic pharmacologically active agent across the blood-brain barrier. The invention is useful with a wide variety of biologically active agents, and administration as a pharmacologically active agent is not accompanied by any noticeable side effects. The invention thus represents a significant advance in the fields of drug delivery and neuropharmacology.

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. Furthermore, the practice of the present invention will employ, unless otherwise indicated, conventional techniques of drug formulation, which are well within the skill of the art. Such techniques are fully explained in the literature. See Remington: The Science and Practice of Pharmacy, cited supra, as well as Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed. (New York: McGraw-Hill, 1996).

Claim 1 of 76 Claims

What is claimed is:

1. A method for increasing the solubility of an ionizable compound in a lipophilic medium, wherein ionization of the compound results in a biologically active cationic species in association with an anionic counterion, the method comprising admixing the ionizable compound with an effective solubility enhancing amount of an N,N-dinitramide salt.

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