(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/047562 A2 27 March 2014 (27.03.2014) P O P C T

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 31/675 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US20 13/06 1190 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, 23 September 2013 (23.09.201 3) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (25) Filing Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, (26) Publication Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (30) Priority Data: ZW. 61/703,981 2 1 September 2012 (21.09.2012) US (84) Designated States (unless otherwise indicated, for every (71) Applicant: EPIPHANY BIOSCIENCES [US/US]; One kind of regional protection available): ARIPO (BW, GH, California Street, Suite 2800, San Francisco, California GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 941 11 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, (71) Applicants : Volinsky, Fred [US/US]; One California MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Street, Suite 2800, San Francisco, California 941 11 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, DONG, Steven [US/US]; One California Street, Suite KM, ML, MR, NE, SN, TD, TG). 2800, San Francisco, California 941 11 (US). Published: (74) Agent: DITTHAVONG MORI & STEINER, P.C.; 44 Canal Center Plaza, Suite 322, Alexandria, Virginia 223 14 — without international search report and to be republished (US). upon receipt of that report (Rule 48.2(g))

<

©

- (54) Title: METHOD OF TREATING AND/OR PREVENTING SHINGLES AND METHOD OF TREATING AND/OR PRE- © VENTING ZOSTER ASSOCIATED PAIN (57) Abstract: Described herein are methods for the treatment and/or prevention of shingles with antiviral agent or salts, solvates or hydrates thereof. Also described herein are methods for the treatment and/or prevention of post herpetic neuralgia with antiviral agents or salts, hydrates or solvates thereof. METHOD OF TREATING AND/OR PREVENTING SHINGLES AND METHOD OF TREATING AND/OR PREVENTING ZOSTER ASSOCIATED PAIN

by

Steven Dong & Fred Volinsky

CROSS-REFERENCES

[0001] This application claims the benefit of United States Provisional Application Serial No. 61/703,981 by Steven Dong and Fred Volinsky, filed September

2 1, 201 3 and entitled "Method of Treating and/or Preventing Shingles and Methods of Treating and/or Preventing Postherpetic Neuralgia," the contents of which are incorporated herein by this reference.

FIELD OF THE INVENTION [0002] Described herein are methods for the treatment and/or prevention of shingles with antiviral agent or salts, solvates or hydrates thereof. Also described herein are methods for the treatment and/or prevention of post herpetic neuralgia with antiviral agents or salts, hydrates or solvates thereof.

BACKGROUND OF THE INVENTION

[0003] An estimated one million individuals in the United States alone develop herpes zoster (i.e., shingles) each year and the lifetime risk for each individual is estimated to be between about 10% and 20%. Shingles is caused by reactivation of varicella zoster virus (VZV) which infects nearly all humans. The virus is latent in sensory ganglia following primary which usually causes chicken pox.

[0004] Shingles is characterized by a painful blistering skin rash in one or two dermatomes innervated by spinal or cranial nerve and associated pain. Shingles affects individuals of all ages but is most commonly observed in adults fifty years or older with the incidence increasing in older age groups and in individuals with compromised immune systems. [0005] Prodromal rash is the most obvious symptoms of shingles but, however, the VZV associated pain that accompanies viral reactivation requires, by far, the most medical intervention. Pain is typically triggered by the onset of viral replication in neuronal cells and in many situations this pain persists as zoster associated pain (ZAP). ZAP after 120 days is called postherpetic neuralgia (PHN), which is well beyond the clearing of rash and control of viral replication. [0006] ZAP and PHN impacts elderly patients most significantly since approximately 60% of shingles patients over age 60 develop PHN. However, current treatment of PHN, which relies on neuroleptics and analgesics, is frequently ineffective and also fails to treat the underlying cause of pain. [0007] Current treatment of acute herpes zoster is directed to inhibition of VZV replication with antiviral agents which usually leads to diminishment of the severity and duration of shingles. Common shingles treatments are valacyclovir ( 1 000 mg, TID) or (500 mg, TID) or acyclovir (800 mg, 5 times daily) for 7 or ten days. A significant issue with the current therapy is the multiple daily dosing which leads to a lower rate of compliance and a poorer quality of life particularly with elderly patients.

Further, current treatment regimens are not particularly effective in elderly patients and in treating post herpetic neuralgia. [0008] Accordingly, what is needed are antiviral agents, which ideally are dosed once daily and are particularly effective in treating older patients and patients suffering from or subject to post-herpetic neuralgia.

SUMMARY OF THE INVENTION [0009] The current invention satisfies these and other needs by providing antiviral agent or salts, solvates or hydrates thereof for the treatment and/or prevention of shingles and for the treatment and/or prevention of post herpetic neuralgia with antiviral agents or salts, hydrates or solvates thereof. [0010] In one aspect, a method of treating or preventing shingles, shingles pain, or post-herpetic neuralgia in a subject is provided. The method comprises administering an antiviral agent or salts, hydrates, or solvates thereof to a subject in need thereof provided that the antiviral agent is not

02P(0)C02H or 02P(0)CH2C02H

[0011] In another aspect, a method of treating or preventing shingles, shingles pain, or post-herpetic neuralgia in a subject is provided. The method comprises administering an antiviral agent or salts, hydrates, or solvates thereof to a subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is an antiviral agent selected from the group consisting of valomaciclovir stearate (EPB-348), octadecyloxyethyl- (ODE-CDV,

CMX-001 ), hexadecyloxypropyl-cidofovir (HDP-CDV), abacavir, , , amprenavir, arbidol, atzanavir, atripla, combivir, darunavir, delavirdine, didanosine, docosanol, , efavirenz, emtricitabine, enfuvirtide, , entry inhibitors, antiretroviral, , fosamprenavir, fusion inhibitors, gardasil, ibacitabine, imunovir, , , indinavir, , integrase inhibitor, type III, interferon type II, interferon type I, interferon, , lopinavir, lopinavir, loviride, MK-051 8, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, , , , , protease inhibitors, reverse transcriptase inhibitors, , , , saquinavir, stavudine, synergistic enhancer, tenofovir, tenofovir disproxil, tipranavir, , trizivir, , truvada, valavivlovir, vicriviroc, , viramidine, zalcitabine, , zidovudine, A-5021 ([1 'S,2'R)-9[[1 '2'-bis(hydroxymethyl)cycloprop-1 '-yl]- methyl]]), cyclopropavir (CPV, ZSM-l-62), 2,4-diamino-6-R43-hydroxy- 2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), N-(4-chlorobenzyl)-1 - methyl-6-(4-morpholinylmethyl)-4-oxo-1 ,4-dihydro-3-quinolinecarboxamide (PNU- 183792), 2-bromo-5,6-dichloro-1 -(beta-D-ribofuranosyl)benzimidazole (BDCRB), 1- (beta-L-ribofuranosyl)-2-isopropylamino-5,6-dichlorobenzimidazole (, 1263W94), 3-hydroxy-2,2-dimethyl-N[4-{ [(5-dimethylamino)-1 - naphthylj-sulfonyl}- amino)phenyl}propamide (BAY 38-4766), 4-(2-amino-4- thiazolyl)phenyl derivative (BILS 79BS), N45-(aminosulfonyl)-4-methyl-1 ,3- thiazol-2-yl]-N-methyl-2-{4-(2- pyridinyl)phenyl}acetamide (BAY 57-1 293), 2H-3-(4-chlorophenyl)-3,4-dihydro-1 ,4- benzo-thiazine-2-carbonitrile-1 -oxide or 1, 1 -dioxide and 2-chloro-3-pyridin-3-yl-5, 6,7,8- tetrahydronindolizine-1 -carboxamide (CMV423).

[0012] In yet another aspect, a method of treating or preventing shingles, shingles pain, or post-herpetic neuralgia in a subject is provided. The method comprises administering an antiviral agent or salts, hydrates, or solvates thereof to a subject in need thereof a therapeutically effective quantity of an antiviral agent, wherein the antiviral agent is a compound of Formula (I):

(I) wherein:

(i) R is hydrogen, hydroxy, mercapto, or amino;

(ii) R 2 is hydrogen, hydroxy, fluoro, chloro, or amino;

(iii) R 3 and R 4 are inde endently selected from

amino, hydroxy, or an ether or ester residue thereof, or R 3 together with R is

wherein: M is hydrogen; and n is 1 or 2 with the proviso that when R 2 is amino and R 3 and R 4 are hydroxy, R i is not hydroxy, and, in addition, when n is 1, R 2 is not hydrogen; or a salt, solvate, hydrate, or mixture thereof.

[0013] In another aspect, a method of treating or preventing shingles, shingles pain, or post-herpetic neuralgia in a subject is provided. The method comprises administering an antiviral agent or salts, hydrates, or solvates thereof to a subject in need thereof a therapeutically effective amount of a compound of Formula (II): 2

(II). [0014] or salts, solvates or hydrates thereof, wherein:

( 1) in a first alternative, R is hydrogen, -C(O)CH(CH(CH 3)2)NH2 or - CH3)NH is C(O)CH(CH(CH3)CH2 2; R2 hydrogen o -C(O)C 3-C2 1 saturated or monounsaturated, optionally substituted alkyl; and R 3 is OH or H; or

(2) in a second alternative, Ri is hydrogen o -C(O)C3-C 2i saturated or monounsaturated, optionally substituted alkyl; R2 is hydrogen, -C(O)CH(CH(CH 3)2)NH2 or -C(O)CH(CH(CH 3)CH 2CH3)NH 2; and R3 is OH or H . [0015] In yet another aspect, a method of treating or preventing shingles, shingles pain, or post-herpetic neuralgia in a subject is provided. The method comprises administering an antiviral agent or salts, hydrates, or solvates thereof to a subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is valomaciclovir stearate (Formula (III)):

[0016] In yet another aspect, a method of treating or preventing shingles, shingles pain, or post-herpetic neuralgia in a subject is provided. The method comprises administering an antiviral agent or salts, hydrates, or solvates thereof to a subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is a compound of Formula (IV):

(IV) wherein, in Formula (IV), the antiviral compound is selected from the group consisting of:

( 1) the compound wherein R is H and R2 is H, and the compound is (R)- 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V))

(V); 2 (2) the compound wherein R is P(O)(OH)2 and R is H, and the compound is H2G-monophosphate (Formula (VI)) 2 (3) the compound wherein R is P(O)(OH)-O-P(O)(OH) 2 and R is H, and the compound is H2G-diphosphate (Formula (VII))

1 (4) the compound wherein R is P(O)(OH)-O-P(O)(OH)-O-P(O)(OH) 2 and R2 is H, and the compound is H2G-triphosphate (Formula (VIII))

2 (5) the compound wherein R is H and R is P(O)(OH)2 (Formula (IX) (ix); 2 (6) the compound wherein R is H and R is P(O)(OH)-O-P(O)(OH) 2 (Formula (X));

(X); and

(7) the compound wherein R is H and R2 is P(O)(OH)-O-P(O)(OH)-O-

P(O)(OH)2 (Formula (XI) (XI). [0017] Another aspect of the invention is a pharmaceutical composition comprising:

( 1) an antiviral agent or a salt, solvate, or hydrate thereof as described above; (2) a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION [0018] Definitions [0019] "Compounds" refers to compounds encompassed by structural formulae disclosed herein and includes any specific compounds within these formulae whose structure is disclosed herein. Compounds may be identified either by their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof, in cases wherein the chemistry allows for keto-enol tautomerism or other forms of tautomerism. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. The compounds described also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to, 2H, 3H, 3C, 4 C, 5 N, 0, 0, and other known isotopes; these isotopes may be stable and non-radioactive, as in the case of deuterium (2H), or may be radioactive, as in the case of tritium (3H). Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. The compounds may be isolated in crystal form, preferably homogenous crystals, and thus the compounds of Formula I may be provided in substantially pure crystalline form, comprising >70%, preferably >90% homogeneous crystalline material for example >95% homogeneous crystalline material. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention. [0020] "Alkyl," by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene, or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1 -yl, propan-2-yl, cyclopropan-1 -yl, prop-1 -en-1 -yl, prop-1 -en-2-yl, prop-2-en-1 -yl (allyl), cycloprop-1 -en-1 - yl; cycloprop-2-en-1 -yl, prop-1 -yn-1 -yl, prop-2-yn-1 -yl, and other groups known in the art; butyls such as butan-1 -yl, butan-2-yl, 2-methyl-propan-1 -yl, 2-methyl-propan-2-yl, cyclobutan-1 -yl, but-1 -en-1 -yl, but-1 -en-2-yl, 2-methyl-prop-1 -en-1 -yl, but-2-en-1 -yl, but- 2-en-2-yl, buta-1 ,3-dien-1 -yl, buta-1 ,3-dien-2-yl, cyclobut-1 -en-1 -yl, cyclobut-1 -en-3-yl, cyclobuta-1 ,3-dien-1 -yl, but-1 -yn- -yl, but-1 -yn-3-yl, but-3-yn-1 -yl, and other groups known in the art. The term "alkyl," as used herein, is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions "alkanyl," "alkenyl," or "alkynyl" are used. In some embodiments, an alkyl group comprises from 1 to 20 carbon atoms (CrC 2oalkyl). In other embodiments, an alkyl group comprises from 1 to 10 carbon atoms (C1-C10 alkyl). In still other embodiments, an alkyl group comprises from 1 to 6 carbon atoms (C1-C6 alkyl). [0021] "Alkanyl," by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1 -yl, propan-2-yl

(isopropyl), cyclopropan-1 -yl, and other groups known in the art; and butanyls such as butan-1 -yl, butan-2-yl (sec-butyl), 2-methyl-propan-1 -yl (isobutyl), 2-methyl-propan-2-yl

(f-butyl), cyclobutan-1 -yl, and other groups known in the art. [0022] "Alkenyl," by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon- carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s) unless a specific conformation is specified. Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1 -en-1 -yl, prop-1 -en-2-yl, prop-2-en-1 -yl (allyl), prop-2-en-2-yl, cycloprop-1 -en-1 -yl; cycloprop-2-en-1 -yl; butenyls such as but-1 -en-1 -yl, but-1 -en-2-yl, 2-methyl-prop-1 -en-1 -yl, but-2-en-1 -yl, but-2-en-1 - yl, but-2-en-2-yl, buta-1 ,3-dien-1 -yl, buta-1 ,3-dien-2-yl, cyclobut-1 -en-1 -yl, cyclobut-1 - en-3-yl, cyclobuta-1 ,3-dien-1 -yl, and other groups known in the art. [0023] "Alkynyl," by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon- carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1 -yn-1 -yl, prop-2-yn-1 -yl, and other groups known in the art; butynyls such as but- -yn-1 -yl, but-1 -yn-3-yl, but-3-yn-1 -yl, and other groups known in the art. [0024] "Alkoxy," by itself or part of another substituent, refers to a radical of the formula -O-R 400 , wherein R400 is alkyl as defined herein. [0025] "Alkoxyalkyl," by itself or part of another substituent, refers to a radical of the formula, refers to a radical of the formula - R400-O-R401 , wherein R40 is alkyl as defined herein. [0026] "Aryl," by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. In some embodiments, an aryl group comprises from 6 to 20 carbon atoms (C6-C2oaryl)- In other embodiments, an aryl group comprises from 6 to 15 carbon atoms (C6-Ci 5 aryl). In still other embodiments, an aryl group comprises from 6 to 15 carbon atoms (C6-Ci 0 aryl). [0027] "Arylalkyl," by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl group as, as defined herein. Typical arylalkyi groups include, but are not limited to, benzyl, 2-phenylethan-1 -yl, 2- phenylethen-1 -yl, naphthylmethyl, 2-naphthylethan-1 -yl, 2-naphthylethen-1 -yl, naphthobenzyl, 2-naphthophenylethan-1 -yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used. In some embodiments, an arylalkyi group is (C6-C30) arylalkyi, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyi group is (C1 -C10) alkyl and the aryl moiety is (C 6-C 2o) aryl.

In other embodiments, an arylalkyi group is (C 6-C 2o) arylalkyi, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyi group is (CrCs) alkyl and the aryl moiety is (C6-C12) aryl. In still other embodiments, an arylalkyi group is (C6-C1 5) arylalkyi, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyi group is (C1 -C5) alkyl and the aryl moiety is (C 6- C10) aryl.

[0028] In chemical formulas presented herein, either subscripts ("R ) or superscripts ("R ") can be used to designate particular chemical groups or moieties. These are deemed to be equivalent for the purposes of such designation. [0029] The term "salts" as used herein refers to salts of the compounds disclosed herein such as, for example, salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3- phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2- napthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p- toluenesulfonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric and sulfonic acids. In many alternatives, hydrochloric acid salts are convenient. In some alternatives, particular salts are chosen to enhance bioavailability or tolerance of particular cells, organs, or tissues. [0030] The term "vehicle" as used herein refers to a diluent, adjuvant, excipient or carrier with which an antiviral agent is administered. [0031] The terms "subject," "individual," or "patient" as used herein are used interchangeably herein and refer to a vertebrate, preferably a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals and pets. [0032] The terms "preventing" or "prevention" as used herein refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease). [0033] The terms "treating" or "treatment" of any disease or disorder refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In other embodiments "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet other embodiments, "treating" or "treatment" refers to inhibiting the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter) or both. In yet other embodiments, "treating" or "treatment" refers to delaying the onset of the disease or disorder. [0034] The term "therapeutically effective amount" as used herein means the amount of an antiviral agent or other compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The amount of the antiviral agent or other compound considered a "therapeutically effective amount" will vary depending on the antiviral agent or other compound the disease and its severity and the age, weight, etc., of the subject to be treated. [0035] As used herein, the term "prodrug" refers to compounds that are transformed in vivo to yield a disclosed compound or a pharmaceutically acceptable form of the compound. In some embodiments, a prodrug is a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound as described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug can be inactive when administered to a subject, but is then converted in vivo to an active compound, for example, by hydrolysis (e.g., hydrolysis in blood or a tissue). In certain cases, a prodrug has improved physical and/or delivery properties over a parent compound from which the prodrug has been derived. The prodrug often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (H. Bundgard, Design of Prodrugs (Elsevier, Amsterdam, 1988), pp. 7-9, 2 1-

24), incorporated herein by this reference. A discussion of prodrugs is provided in T. Higuchi et al., "Pro-Drugs as Novel Delivery Systems," ACS Symposium Series , Vol. 14 and in E.B. Roche, ed., Bioreversible Carriers in Drug Design (American Pharmaceutical Association & Pergamon Press, 1987), both incorporated herein by this reference. Exemplary advantages of a prodrug can include, but are not limited to, its physical properties, such as enhanced water solubility for parenteral administration at physiological pH compared to the parent compound, enhanced absorption from the digestive tract, or enhanced drug stability for long-term storage. [0036] The term "prodrug" is also meant to include any covalently bonded carriers which release the active compound in vivo when the prodrug is administered to a subject. Prodrugs of a therapeutically active compound, as described herein, can be prepared by modifying one or more functional groups present in the therapeutically active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent therapeutically active compound. Prodrugs include compounds wherein a hydroxy, amino, or mercapto group is covalently bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, formate or benzoate derivatives of an alcohol or acetamide, formamide or benzamide derivatives of a therapeutically active agent possessing an amine functional group available for reaction, and the like. [0038] For example, if a therapeutically active agent or a pharmaceutically acceptable form of a therapeutically active agent contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the carboxylic acid group with a group such as -s alkyl, C2-12 alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1 - (alkanoyloxy)ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1 -(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N(Ci -C2 )alkylamino(C2-C3 )alkyl (such as

(3-dimethylaminoethyl), carbamoyl-(Ci -C2 )alkyl, N,N-di (Ci -C2 )alkylcarbamoyl-(Ci -

C 2)alkyl and piperidino-, pyrrolidino-, or morpholino(C 2-C 3)alkyl. [0039] Similarly, if a disclosed compound or a pharmaceutically acceptable form of the compound contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as (Ci -

C 6)alkanoyloxymethyl, 1-((CrC 6))alkanoyloxy)ethyl, 1-methyl-1 -((C

C 6)alkanoyloxy)ethyl (Ci -C 6)alkoxycarbonyloxymethyl, N( -

C 6)alkoxycarbonylaminomethyl, succinoyl, (CrC 6)alkanoyl, a -amino(Ci -C )alkanoyl, arylacyl and a -aminoacyl, or a -aminoacyl-a-aminoacyl, where each a -aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH) 2,

P(O)(O(Ci -C6 )alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate). [0040] If a disclosed compound or a pharmaceutically acceptable form of the compound incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl,

RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci -Ci 0)alkyl, (C 3- α C 7)cycloalkyl, benzyl, or R-carbonyl is a natural -aminoacyl or natural a -aminoacyl- α 1 2 3 natural -aminoacyl, C (OH)C(O)OY wherein Y is H, (C C 6)alkyl or benzyl, C (OY )Y 2 3 wherein Y is (CrC ) alkyl and Y is (CrC 6)alkyl, carboxy(CrC 6)alkyl, amino(Ci -C )alkyl 4 5 4 5 or mono-N or di-N,N(Ci-C 6)alkylaminoalkyl,C(Y )Y wherein Y is H or methyl and Y is mono-N or di-N,N(Ci-C6)alkylamino, morpholino, piperidin-1 -yl or pyrrolidin-1 -yl.

[0041] The use of prodrug systems is described in T. Jarvinen et al., "Design and

Pharmaceutical Applications of Prodrugs" in Drug Discovery Handbook (S.C. Gad, ed., Wiley-lnterscience, Hoboken, NJ, 2005), ch. 17, pp. 733-796, incorporated herein by this reference. [0042] Methods of Treating and/or Preventing Shingles

[0043] In practicing the method of treating and/or preventing shingles, therapeutically effective amounts of the compounds described below are administered to a subject in need of treatment and prevention.

[0044] In some embodiments, an antiviral agent or salts, hydrates, or solvates thereof to a subject in need thereof provided that the antiviral agent is not 2 1 02P(0)C02H or 02P(0)CH2C02H

[0045] In other embodiments, the antiviral agent is a compound of Formula (I)

salts, solvates, hydrates, or mixtures thereof, wherein:

(i) R is hydrogen, hydroxy, mercapto, or amino; R2 is hydrogen, hydroxy, fluoro, chloro, or amino

R3 and R are independently selected from

amino, hydroxy, or an ether or ester residue thereof, or R 3 together with R is

O

p .

OM

wherein: M is hydrogen; and n is 1 or 2 with the proviso that when R2 is amino and R3 and R are hydroxy, R is not hydroxy, and, in addition, when n is 1, R2 is not hydrogen. [0046] The compounds of Formula (I) above contain one asymmetric center when C H2, C H R3, and (CH )nR4 are different. [0047] Exemplary antiviral agents are those wherein and R are independently hydrogen, hydroxy, or amino, and wherein R3 is

hydroxy or an ester derivative thereof, and R4 is O H or an ester derivative thereof or wherein R3 and R together are [0048] In some embodiments, R 3 and R4 are both hydroxy. [0049] In some embodiments, compounds of Formula (I) include the following

salts, solvates, hydrates, or mixtures thereof wherein: R = OH, R2 = N¾, R3 = OH, R4 OH;

R = H, R2 = NIi , R3 = OH, R4 = OH;

R N¾ R2 ¾ R3 = OH, R4 = OH;

2 3 4 OH, R NII , R = OCOC -3 , R = OCOC1-3;

2 3 4 H, R = NH2, R = OCOC1.3, R = OCOC1-3; R = NH , R2 = H, R3 4 2 = OCOC 1-3 , R = OCOC1.3 ;

R = OH, R2 = NH , R3 = OCONH-phenyl,R 4 = OCONH-phenyl;

R = H, R2 = NH , R3 = OCONH-phenyl, R4 = OCONH-phenyl; and

R1 = NH , R2 = H, R3 = OCONH-phenyl, R4 = OCONH-phenyl; and derivatives and analogs thereof. [0050] Esters and ethers of the above compounds are also useful antiviral agents. Examples of esters are phosphate esters, carboxylic esters, carbonate esters, carbamate esters o r sulfonic esters. The acid part of the esters may have alkyl, aryl o r arylalkyi chains, where the aryl functionalities are optionally substituted for example by alkoxy, amino, nitrile, alkyl o r sulfonamido groups o r by one o r more halogen atoms. [0051] Other types of derivatives of the above compounds which may be useful as antiviral agents include alkyl o r arylalkyi derivatives of the primary hydroxyl group(s). The arylalkyi ether derivatives may be for example benzyl o r triphenyl methyl and the aryl moiety may be optionally substituted.

[0052] In compounds of Formula I, R3 and R4 as an ether residue can be defined as O R5, wherein R5 is -6 alkyl, arylalkyi optionally substituted with one o r more alkoxy, amino, nitrile o r sulfamido groups o r one o r more halogen atoms. In some embodiments, R3 and R4 as an ester residue can be derived from a carboxylic acid R6COOH, a carbonic acid R OCOOH, a double ester of a carbonic acid

R CO 2CH(R )OCO 2H, a sulfonic acid R SO 2OH, a carbamic acid R NHCOOH o r a 6 7 phosphoric acid, wherein R is hydrogen, C 7 alkyl, alkoxyalkyl, arylalkyi o r aryl, R is

8 C - 7 alkyl, arylalkyi o r aryl, R is hydrogen o r Ci-i 3 alkyl and the aryl and arylalkyi groups are optionally substituted with one o r more alkyl, alkoxy, amino, nitrile, o r halogen groups. [0053] Other useful antiviral agents include those of Formula (I), below: (I) or salts, solvates, hydrates, or mixtures thereof wherein:

(i) Ri is hydrogen, hydroxy, mercapto or amino;

(ii) R2 is hydrogen, hydroxy, fluoro, chloro, or amino;

(iii) R3 and R are independently selected from

, hydroxy, or an ether or ester residue thereof, or R3 together with R

wherein: M is hydrogen; and n is 1 or 2 with the proviso that when R2 is amino and R 3 and R are hydroxy, R is not hydroxy, and, in addition, when n is 1, R2 is not hydrogen. [0054] In some embodiments, the antiviral agent is valomaciclovir stearate

(EPB-348), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001 ), hexadecyloxypropyl- cidofovir (HDP-CDV), abacavir, adefovir, amantadine, amprenavir, arbidol, atzanavir, atripla, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, entry inhibitors, antiretroviral, fomivirsen, fosamprenavir, fusion inhibitors, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type

I, interferon, lamivudine, lopinavir, lopinavir, loviride, MK-051 8, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, synergistic enhancer, tenofovir, tenofovir disproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valavivlovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, A-5021 ([1 'S,2'R)-9[[1 '2'- bis(hydroxymethyl)cycloprop-1 '-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-l-62), 2,4-diamino-6-R43-hydroxy-2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), N-(4-chlorobenzyl)-1 -methyl-6-(4-morpholinylmethyl)-4-oxo-1 ,4-dihydro-3- quinolinecarboxamide (PNU-1 83792), 2-bromo-5,6-dichloro-1 -(beta-D- ribofuranosyl)benzimidazole (BDCRB), 1-(beta-L-ribofuranosyl)-2-isopropylamino-5,6- dichlorobenzimidazole (Maribavir, 1263W94), 3-hydroxy-2,2-dimethyl-N[4-{ [(5- dimethylamino)-1 - naphthyl]-sulfonyl}-amino)phenyl}propamide (BAY 38-4766), 4-(2- amino-4- thiazolyl)phenyl derivative (BILS 179BS), N45-(aminosulfonyl)-4-methyl-1 ,3- thiazol-2-yl]-N-methyl-2-{4-(2-pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4- chlorophenyl)-3,4-dihydro-1 ,4-benzo-thiazine-2-carbonitrile-1 -oxide or 1, 1 -dioxide or 2- chloro-3-pyridin-3-yl-5,6,7,8-tetrahydronindolizine-1 -carboxamide (CMV423), or a salt, solvate, or hydrate thereof.

[0055] In some embodiments, the antiviral agent is valomaciclovir stearate.

[0056] In other embodiments, the antiviral agent is omaciclovir, valomaciclovir stearate (EPB-348), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001 ) or hexadecyloxypropyl-cidofovir (HDP-CDV).

[0057] In still other embodiments, the antiviral agent is octadecyloxyethyl- cidofovir (ODE-CDV, CMX-001 ), hexadecyloxypropyl-cidofovir (HDP-CDV), A-5021

([1 'S, 2'R)-9[[1 '2'-bis(hydroxymethyl)cycloprop-1 '-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-l-62), 2,4-diamino-6-R[3-hydroxy-2-(phosphonomethoxy)propoxy}- pyrimidine (HPMPO-DaPy), HPMPA, 3-Deaza-HPMPA, N-(4-chlorobenzyl)-1 -methyl-6- (4-morpholinylnnethyl)-4-oxo-1 ,4-dihydro-3-quinolinecarboxamide (PNU-1 83792), 2- Bromo-5,6-dichloro-1 -(beta-D-ribofuranosyl)benzinnidazole (BDCRB), 1-(beta-L- ribofuranosyl)-2-isopropylannino-5,6-dichlorobenzinnidazole (Maribavir, 1263W94), 3- hydroxy-2,2-dimethyl-N[4-{ [(5-dimethylamino)-1 -naphthyl]-sulfonyl}- amino)phenyl}propannide (BAY 38-4766), 4-(2-amino-4-thiazolyl)phenyl derivative (BIB 79BS), N45-(aminosulfonyl)-4-methyl-1 ,3-thiazol-2-yl]-N-methyl-2-{4-(2- pyridinyl)phenyl}acetamide (BAY 57-1 293), 2H-3-(4- chlorophenyl)-3,4-dihydro-1 ,4- benzo-thiazine-2-carbonitrile-1 , 1 -dioxide or 2-chloro-3-pyridin-3-yl-5, 6,7,8- tetrahydronindolizine-1 -carboxamide (CMV423).

[0058] In some embodiments, two or more antiviral agents can be employed.

[0059] In some embodiments, the antiviral agent is two or more of valomaciclovir stearate (EPB-348), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001 ), hexadecyloxypropyl-cidofovir (HDP-CDV), abacavir, adefovir, amantadine, amprenavir, arbidol, atzanavir, atripla, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efa virenz, emtricitabine, enfuvirtide, entecavir, entry inhibitors, antiretroviral, fomivirsen, fosamprenavir, fusion inhibitors, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, lopinavir, loviride, MK-051 8, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, synergistic enhancer, tenofovir, tenofovir disproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valavivlovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, A-5021 ([1 'S, 2'R)-9[[1 '2'-bis(hydroxymethyl)cycloprop-1 '-yl]- methyl]guanine]), cyclopropavir (CPV, ZSM-l-62), 2,4-diamino-6-R43-hydroxy- 2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), cyclopropavir (CPV, ZSM-l- 62), N-(4-chlorobenzyl)-1 -methyl-6-(4-morpholinylmethyl)-4-oxo-1 ,4-dihydro-3- quinolinecarboxamide (PNU-1 83792), 2-bromo-5,6-dichloro-1 -(beta-D- ribofuranosyl)benzimidazole (BDCRB), 1-(beta-L-ribofuranosyl)-2-isopropylamino-5,6- dichlorobenzimidazole (Maribavir, 1263W94), 3-hydroxy-2,2-dimethyl-N[4-{[(5- dimethylamino)-1 - naphthyl]-sulfonyl}-amino)phenyl}propannide (BAY 38-4766), 4-(2- amino-4- thiazolyl)phenyl derivative (BILS 179BS), N45-(aminosulfonyl)-4-methyl-1 ,3- thiazol-2-yl]-N-methyl-2-{4-(2-pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4- chlorophenyl)-3,4-dihydro-1 ,4-benzo-thiazine-2-carbonitrile-1 -oxide or 1, 1 -dioxide or 2- chloro-3-pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1 -carboxamide (CMV423).

[0060] In still other embodiments, the antiviral agents is two or more of omaciclovir, valomaciclovir stearate (EPB-348), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001 ) or hexadecyloxypropyl-cidofovir (HDP-CDV).

[0061] In still other embodiments, the antiviral agents are two or more of octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001 ), hexadecyloxypropyl-cidofovir (HDP-

CDV), A-5021 ([1 'S, 2'R)-9[[1 '2'-bis(hydroxymethyl)cycloprop-1 '-yl]-methyl]guanine]), cydopropavir (CPV, ZSM-l-62), 2,4-diamino-6-R[3-hydroxy-2- (phosphonomethoxy)propoxy}-pyrimidine (HPMPO-DaPy), HPMPA, 3-Deaza-HPMPA, cydopropavir (CPV, ZSM-l-62), N-(4-chlorobenzyl)-1 -methyl-6-(4-morpholinylmethyl)-4- oxo-1 ,4-dihydro-3-quinolinecarboxamide (PNU-1 83792), 2-Bromo-5,6-dichloro-1 -(beta- D-ribofuranosyl)benzimidazole (BDCRB), 1-(beta-L-ribofuranosyl)-2-isopropylamino-5,6- dichlorobenzimidazole (Maribavir, 1263W94), 3-hydroxy-2,2-dimethyl-N[4-{[(5- dimethylamino)-1 -naphthyl]-sulfonyl}-amino)phenyl}propamide (BAY 38-4766), 4-(2- amino-4-thiazolyl)phenyl derivative (BIB 179BS), N45-(aminosulfonyl)-4-methyl-1 ,3- thiazol-2-yl]-N-methyl-2-{4-(2-pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4- chlorophenyl)-3,4-dihydro-1 ,4-benzo-thiazine-2-carbonitrile-1 , 1 -dioxide or 2-chloro-3- pyridin-3-yl-5,6,7,8-tetrahydroindolizine-1 -carboxamide (CMV423).

[0062] In some embodiments, antiviral agents include the compound of Formula (II): or salts, solvates, hydrates or mixtures wherein:

( 1) in a first alternative, R is hydrogen, -C(O)CH(CH(CH 3)2)NH 2 or -

C(O)CH(CH(CH3)CH 2CH3)NH 2; R is hydrogen or -C(0)C 3-C2i saturated or monounsaturated, optionally substituted alkyl; and R 3 is O H or H; or

(2) in a second alternative, R is hydrogen o -C(O)C 3-C saturated or monounsaturated, optionally substituted alkyl; R2 is hydrogen, -C(O)CH(CH(CH 3)2)NH or -C(O)CH(CH(CH 3)CH 2C H3)NH 2; and R3 is O H or H . [0063] In some embodiments, the compounds of Formula (II) are at least between about 70% and about 90% form. In other embodiments, the compounds of

Formula (II) are greater than about 95% the R form. In still other embodiments, the compounds of Formula (II) are greater than about 99% the R form. In still other embodiments, the compounds of Formula (II) are greater than about 99.9 % the form.

[0064] In some embodiments, the amino acid of group R and/or R is derived from an L-amino acid.

[0065] In some embodiments, the fatty acid of group R and/or R groups have in total an even number of carbon atoms, in particular, decanoyl (C10), lauryl (Ci 2),

) , myristoyl (Ci 4 palmitoyl (C ), stearoyi (Cis) or eicosanoyi (C 2o). In other embodiments, R and/or R groups include butyryl, hexanoyl, octanoyl or behenoyl (C ). In still other embodiments, the R and/or R groups include those derived from myristoleic, myristelaidic, palmitoleic, palmitelaidic, n6-octadecenoic, oleic, elaidic, gandoic, erucic or brassidic acids. Monounsaturated fatty acid esters typically have the double bond in the trans configuration, preferably in the -6, -9, or -1 1 position, dependent on their length. In some embodiments, the R and/or R2 groups are derived from a fatty acid which comprises a C g to C 17 saturated, or n:9 monounsaturated alkyl.

[0066] In some embodiments, the saturated or unsaturated fatty acid or R and/or R2 groups may optionally be substituted with up to five similar or different substituents including those such as hydroxy, CrC 6 alkyl, CrC 6 alkoxy, CrC 6 alkanoyi, amino, halo, cyano, azido, oxo, mercapto and nitro, and the like.

[0067] In some embodiments, Ri is -C(O)CH(CH 3)2)NH 2 or - In C(O)CH(CH(CH 3)CH2CH3)NH2 and R2 is -C(O)C9-C17 saturated alkyl. other embodiments, R and R are hydrogen.

[0068] In some embodiments, the compounds of Formula (II) include: (R)-9-[2- (butyryloxymethyl)-4-(L-isoleucyloxy)butyl]guanine, (R)-9-[2-(4-acetylbutyryloxymethyl)- 4-(L-isoleucyloxy)butyl]guanine, (R)-9[2-(hexanoyloxymethyl)-4-(L- isoleucyloxy)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2- (octanoyloxymethyl)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2- (decanoyloxymethyl)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2- (dodecanoyloxymethyl)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2- (tetradecanoyloxymethyl)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2- (hexadecanoyloxymethyl)butyl]guanine, (R)-9-[4-isoleucyloxy)-2- (octadecanoyloxymethyl)butyl]guanine, (R)-9-[2-(eicosanoyloxymethyl)-4-(L- isoleucyloxy)butyl]guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L- isoleucyloxy)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2-[((9- tetradecenoyl)oxymethyl)butyl]guanine, (R)-9-[2-((9-hexadecenoyl)oxymethyl)-4-(L- isoleucyloxy)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2-((6- octadecenoyl)oxymethyl)butyl]guanine, (R)-9-[4-(L-isoleucyloxy)-2((9- octadecenoyl)oxymethyl)-butyl]guanine, (R)- 9- [2-((11 -eicosanoyl)-oxymethyl)-4- (L- isoleucyloxy)butyl]guanine, (R)-9-[2-((1 3-docosenoyl)-oxymethyl)-4-(L- isoleucyloxy)butyl]guanine, R)-2-amino-9-[2-(butyryloxymethyl)-4- (L-isoleucyloxy)butyl]purine, R)-2-amino-9-[2-(4-acetylbutyryloxymethyl)-4- (L-isoleucyloxy)butyl]purine, (R)-2-amino-9-[2-(hexanoyloxymethyl)-4-(L- isoleucyloxy)butyl]purine, (R)-2-amino-9-[4-L-isoleucyloxy)-2- (octanoyloxymethyl)butyl]purine, (R)-2-amino-944-(L-isoleucyloxy)-2- (decanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (dodecanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- tetradecanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (hexadecanoyloxymethypbutyl]purine, (R)-2-amino-944-(L-isoleucyloxy)-2- (octadecanoyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2- (eicosanoyloxymethyl)butyl]purine, (R)-2-amino-9-[2-(eicosanoyloxymethyl)-4- (L-isoleucyloxy)butyl]purine, (R)-2-amino-9-[2-(docosanoyloxymethyl)-4- (L-isoleucyloxy)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2-((9- tetradecenoyl)oxymethyl)butyl]purine, (R)-2-amino-9-[2((9- hexadecenoyl)oxymethyl)-4- (L-isoleucyloxy)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2-((6- octadecenoyl)oxymethyl)butyl]purine, (R)-2-amino-9-[4-(L-isoleucyloxy)-2-((9- octadecenoyl)oxymethyl)butyl]purine, (R)-2-amino-9- [2-((1 1-eicosanoyl)oxymethyl)-4- (L-isoleucyloxy)butyl]purine and (R)-2-amino-9-[2-((1 3-docosenoyl)oxymethyl)-4-(L- isoleucyloxy)butyl]purine. In other embodiments, the compounds of Formula II include (R)-9-[2-(butyryloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(4- acetylbutyryloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(hexanoyloxymethyl)-4- (L-valyloxy)butyl] guanine, (R)-9[2-(octanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)- 9-[2-(decanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(dodecanoyloxymethyl)- 4-(L-valyloxy)butyl]guanine, (R)-9-[2-(tetradecanoyloxymethyl-4- (L-valyloxy)butyl]guanine, (R)-9-[2-hexadecanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(octadecanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2- (eicosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(eicosanoyloxymethyl)-4-(L- valyloxy)butyl]guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)- 9-[2-((9-tetradecenoyl)oxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-((9- hexadecenoyl)oxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-((6- octadecenoyl)oxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(9- octadecenoyl)oxymethyl)-4-(L-valyloxy)-butyl]guanine, (R)-9-[2-((1 1- eicosanoyl)oxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-((1 3- docosenoyl)oxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-2-amino-9-[2- (butyryloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2-(4-[2- (dodecanoyloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2- (tetradecanoyloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2- (hexadecanoyloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2- (octadecanoyloxymethyl)-4-(L-valyloxy)-butyl]purine, (R)-2-amino-9-[2- (eicosanoyloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9- [2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2-(9- tetradecenoyl)oxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2-((9- hexadecenoyl)oxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2-((6- octadecenoyl)oxymethyl)-4-(L-valyloxy)butyl]purine, (R)-2-amino-9-[2-((9- octadecenoyloxymethyl)-4-(L-valyloxy)-butyl]purine, (R)-2-amino-9-[2-((1 1-eicosenoyl)- oxymethyl)-4-(L-valyloxy)butyl]purine, and (R)-2-amino-9-[2-((1 3-docosenoyl)- oxymethyl)-4-(L-valyloxy)butyl]purine. In still other embodiments, the compounds of Formula (II) include R)-9-[4-(butyryloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-(4- acetylbutyryloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-(hexanoyloxy)-2- (L-valyloxymethyl)butyl]guanine, (R)-9-[4-(octanoyloxy)-2-(L- valyloxymethyl)butyl]guanine, (R)-9-[4-(decanoyloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-(dodecanoyloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4- (tetradecanoyloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-hexadecanoyloxy)-2- (L-valyloxymethyl)butyl]guanine, (R)-9-[4-(octadecanoyloxy)-2-(L-valyloxymethyl)butyl] guanine, (R)-9-[4-(eicosanoyloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4- (docosanoyloxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-((9-tetradecenoyl)oxy)-2- (L-valyloxymethyl)butyl]guanine, (R)-9-[4-((9-hexadecenoyl)oxy)-2-(L- valyloxymethyl)butyl]guanine, (R)-9-[4-((6-octadecenoyl)oxy)-2-(L- valyloxymethyl)butyl]guanine, (R)-9-[4-((9-octadecenoyl)oxy)-2-(L-valyloxymethyl)- butyl]guanine, (R)-9-[4-((1 1-eicosenoyl)oxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-9-[4-

((1 3-docosenoyl)-oxy)-2-(L-valyloxymethyl)butyl]guanine, (R)-2-amino-9-[4-(butyryloxy)- 2-(L-valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(4-acetylbutyryloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(hexanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(octanoyloxy)-2-(L- valyloxymethyl)butyl]purine,(R)-2-amino-9-[4-(decanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(dodecanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(tetradecanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(hexadecanoyloxy)-2-(L- valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-(octadecanoyloxy)-2-(L-valyloxymethyl)- butyl]purine, (R)-2-amino-9-[4-(eicosanoyloxy)-2-(L-valyloxynnethyl)butyl]punne, (R)-2- amino-9-[4-(docosanoyloxy)-2-(L-valyloxynnethyl)butyl]purine, (R)-2-amino-9-[4-((9- tetradecenoyl)oxy)-2-(L-valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((9- hexadecenoyl)oxy)-2-(L-valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((6- octadecenoyl)oxy)-2-(L-valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((9- octadecenoyl)oxy)-2-(L-valyloxymethyl)butyl]purine, (R)-2-amino-9-[4-((1 1- eicosenoyl)oxy)-2-(L-valyloxy)butyl]purine, and (R)-2-amino-9-[2-((1 3- docosenoyl)oxymethyl)-2-(L-valyloxy)butyl]purine. In still other embodiments, the compounds of Formula (II) include R)-9-[2-(stearoyloxymethyl)-4-(L- valyloxy)butyl]guanine, (R)-9-[2-(myristoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9- [2-(oleoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(butyrloyloxymethyl)-4-(L- valyloxy)butyl]guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9- [2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(dodecanoyloxymethyl)- 4-(L-valyloxy)butyl]guanine, (R)-9-[2-(palmitoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L-isoleucyloxy)butyl]guanine, (R)-9-[2-(4- acetylbutryloyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(valyloyloxymethyl)-4-(L- stearoyloxy)butyl]guanine, (R)-9-[4-(isoleucyloxymethyl)-2-(L- stearoyloxyethyl)butyl]guanine and (R)-9-[4-(isoleucyloxymethyl)-2-(L- myristoyloxymethyl)butyl]guanine. In still other embodiments, the compound of Formula

(II) is (R)-9-[2-(stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine. In still other embodiments, the compound of Formula (II) is (R)-9-[4-hydroxy-2- (hydroxymethyl)butyl]guanine. [0069] In any of the above embodiments, valomaciclovir stearate may be present as a particular polymorphic form. In some embodiments, the valomaciclovir stearate polymorph has 2-Θ angles of 22.9° +/- 0.2° and 18.6° +/- 0.2°. In other embodiments, the valomaciclovir stearate polymorph has 2-Θ angles of 22.9° +/- 0.2°,

18.6° +/- 0.2°, 19.5° +/- 0.2°, and 24.3° +/- 0.2°. In still other embodiments, the valomaciclovir stearate polymorph has 2-Θ angles of 22.9° +/- 0.2°, 18.6° +/- 0.2°, 19.5°

+/- 0.2°, 24.3° +/- 0.2°, 20.8° +/- 0.2°, 2 .8° +/- 0.2°, and 27.0° +/- 0.2°. In still other embodiments, the valomaciclovir stearate polymorph has 2-Θ angles of 22.9° +/- 0.2°,

18.6° +/- 0.2°, 19.5° +/- 0.2°, 24.3° +/- 0.2°, 20.8 +/- 0.2°, 2 1 .8° +/- 0.2°, 27.0° +/- 0.2°,

14.7° +/- 0.2°, and 15.5° +/- 0.2°. In still other embodiments, the valomaciclovir stearate polymorph has 2-Θ angles of 22.9° +/- 0.2°, 18.6° +/- 0.2°, 19.5° +/- 0.2°, 24.3° +/- 0.2°,

20.8° +/- 0.2°, 2 1 .8 +/- 0.2°, 27.0 +/- 0.2°, 14.7° +/- 0.2°, 15.5° +/- 0.2°, 25.5° +/- 0.2°, and 29.9° +/- 0.2°.

[0070] In some embodiments, the valomaciclovir stearate polymorph has the characteristic DSC features of an endotherm from about 105°C to about 125°C and centered near 115 °C (typically 20-30 J/g) and a melting endotherm from about 170°C to about 180° C, and centered near 17 1 °C (typically around 20-30 J/g).

[0071] In some embodiments, the valomaciclovir stearate polymorph has a Carr index value range from about 35 to about 50, particle size range from about 10 to about 300 microns, a residue on ignition of not more than 0.2%, moisture content of not more than 1.0%, residual solvents not more than as defined above, or purity of not less than 97%.

[0072] In some embodiments, antiviral agents include valomaciclovir stearate (Formula (III): (III). [0073] Typically, the valomaciclovir stearate is crystalline valomaciclovir stearate having characteristic absorption peaks at 2-Θ angles of 22.9° +/- 0.2°, 18.6° +/- 0.2°,

9.5° +/- 0.2°, 24.3° +/- 0.2°, 20.8° +/- 0.2°, 2 .8° +/- 0.2°, 27.0° +/- 0.2°, 14.7° +/- 0.2°,

15.5° +/- 0.2°, 25.5° +/- 0.2°, and 29.9° +/- 0.2° with Cu Ka radiation in a X-ray powder diffractogram. Typically, the crystalline valomaciclovir stearate is at least 90% pure. Preferably, the crystalline valomaciclovir stearate is at least 95% pure. More preferably, the crystalline valomaciclovir stearate is at least 99% pure.

[0074] In some embodiments, antiviral agents include compounds of Formula (IV):

(IV) wherein, in Formula (IV), the antiviral compound is selected from the group consisting of:

( 1) the compound wherein R is H and R2 is H, and the compound is (R)- 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V)) (V); 2 (2) the compound wherein R is P(O)(OH)2 and R is H, and the compound is H2G-monophosphate (Formula (VI))

2 (3) the compound wherein R is P(O)(OH)-O-P(O)(OH) 2 and R is H, and the compound is H2G-diphosphate (Formula (VII))

(Vll); 1 (4) the compound wherein R is P(O)(OH)-O-P(O)(OH)-O-P(O)(OH) 2 and R2 is H, and the compound is H2G-triphosphate (Formula (VIII)) (VIII); 2 (5) the compound wherein R is H and R is P(O)(OH)2 (Formula (IX)

(ix); 2 (6) the compound wherein R is H and R is P(O)(OH)-O-P(O)(OH) 2 (Formula (X)); 40 [0075] In some alternatives, the antiviral agent or the salt, solvate, or hydrate thereof inhibits the varicella zoster virus (VSV) DNA polymerase enzyme. [0076] Methods of Treating and/or Preventing Post-Herpetic Neuralgia, Shingles, and/or Shingles Pain

[0077] In practicing the methods of treating and/or preventing post herpetic neuralgia and treating and/or preventing shingles or shingles pain therapeutically effective amounts of the compounds described above, including compounds of Formula (I), compounds of Formula (II), the compound of Formula (III), and compounds of Formula (IV) (including compounds of Formula (V), compounds of Formula (VI), compounds of Formula (VII), compounds of Formula (VIII), compounds of Formula (IX), compounds of Formula (X), and compounds of Formula (XI)) above are administered to a subject in need of treatment or prevention. Similarly, it should be understood that the various embodiments of these compounds, , including compounds of Formula (I), compounds of Formula (II), the compound of Formula (III), and compounds of Formula (IV) (including compounds of Formula (V), compounds of Formula (VI), compounds of Formula (VII), compounds of Formula (VIII), compounds of Formula (IX), compounds of Formula (X), and compounds of Formula (XI)), including the valomaciclovir stearate polymorph above, can also be used treat and/or prevent post herpetic neuralgia and treat and/or prevent shingles.

[0078] In some alternatives, when a compound of Formula (II) is used to treat shingles, the subject to whom the treatment is administered is greater than 60 years of age. [0079] Compositions and Methods of Administration [0080] The compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the prevention, treatment, or amelioration of one or more of the symptoms of shingles and a vehicle. The compositions provided herein contain therapeutically effective amounts of one or more of the compounds provided herein that are useful in the treatment or amelioration of one or more of the symptoms of post herpetic neuralgia and a vehicle. Vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration.

[0081] In addition, the compounds may be formulated as the sole active ingredient in the composition or may be combined with other active ingredients.

[0082] The compounds are, in some embodiments, formulated into suitable preparations such as solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations or elixirs, for oral administration or in sterile solutions or suspensions for parenteral administration, as well as transdermal patch preparation and dry powder inhalers. In some embodiments, the compounds described above are formulated into compositions using techniques and procedures well known in the art (see, e.g., Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0083] In the compositions, effective concentrations of one or more compounds or derivatives thereof is (are) mixed with a suitable pharmaceutical vehicle. The compounds may be derivatized as the corresponding salts, esters, enol ethers or esters, acetals, ketals, orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydrates or prodrugs prior to formulation, as described above. The concentrations of the compounds in the compositions are effective for delivery of an amount, upon administration, that treats, prevents, or ameliorates one or more of the symptoms of diseases or disorders associated with associated with viral or inappropriate cell proliferation. In some embodiments, the compositions are formulated for single dosage administration. To formulate a composition, the weight fraction of a compound is dissolved, suspended, dispersed or otherwise mixed in a selected vehicle at an effective concentration such that the treated condition is relieved, prevented, or one or more symptoms are ameliorated.

[0084] The active compound is included in the vehicle in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the subject treated. The therapeutically effective concentration may be determined empirically by testing the compounds in in vitro and in vivo systems well known to those of skill in the art and then extrapolated therefrom for dosages for humans. [0085] The concentration of active compound in the composition will depend on absorption, inactivation and excretion rates of the active compound, the physicochemical characteristics of the compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art. For example, the amount that is delivered is sufficient to ameliorate one or more of the symptoms of diseases or disorders associated with shingles, shingles pain, or post-herpetic neuralgia as described herein.

[0086] In some embodiments, a therapeutically effective dosage should produce a serum concentration of active ingredient of from about 0.1 ng/ml to about 50-1 00

g/ml. The compositions, in other embodiments, should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 2000 mg, and in some embodiments from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form. [0087] When compounds of Formula (II) are administered to treat shingles, the compound may be administered at a dose of between about 500 mg QD and about 3000 mg QD; at a dose of between about 1.0 g QD and about 3.0 g QD; at a dose of between about 1.5 g and about 2.5 g QD; or at a dose of about 2.0 g QD or about 3.0 g QD. [0088] When compounds of Formula (II) are administered to treat shingles, the compound may be first administered 2 days after the appearance of skin rash; first administered 3 days after the appearance of skin rash; or first administered 5 days after the appearance of skin rash. When compounds of Formula (II) are administered to treat shingles in a patient who is greater than about 60 years of age, the compound may be first administered 2 days after the appearance of skin rash; first administered 3 days after the appearance of skin rash; or first administered more than 3 days after the appearance of skin rash. In some alternatives, the compounds of Formula (II), particularly (R)-9-[2-stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine (valomaciclovir stearate), may be first administered more than 5 days after the appearance of skin rash. [0089] In some alternatives, when the compound of Formula (II) is administered to treat shingles, the time to full crusting is about 1 1 days when the compound of Formula (II) is administered at a dose of about 2.0 g QD. Alternatively, the time to full crusting is about 7 days when the compound of Formula (II) is administered at a dose of about 3.0 g QD. [0090] When compounds of Formula (II) are administered to treat post-herpetic neuralgia, the compound of Formula (II) may be administered at a dose of between about 500 mg QD and about 3000 mg QD; at a dose of between about 1.0 g QD and about 3.0 g QD; at a dose of between about 1.5 g and about 2.5 g QD; at a dose of about 2.0 g QD or about 3.0 g QD; or at a dose of about 2.0 g QD. [0091] When compounds of Formula (II) are administered to treat post-herpetic neuralgia, the pain may be present about 28 days after the appearance of skin rash. The pain may be present about 28 days after the appearance of skin rash and the compound of Formula (II) may be administered at a dose of about 2.0 g QD. The pain may be resolved at about 33 days and the compound of Formula (II) may be administered at a dose of about 2.0 g QD.

[0092] In another alternative, a method of treating shingles in a subject comprises administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is valomaciclovir stearate (EPB-348) or another prodrug of H2G and which upon administration is converted to a compound selected from the group consisting of (R)-9- [4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V)), H2G-monophosphate (Formula (VI)), H2G-diphosphate (Formula (VII), H2G-triphosphate (Formula (VIII), the compound of Formula (IX), the compound of Formula (X), and the compound of

Formula (XI). In this method, the antiviral agent or the salt, solvate, or hydrate thereof can inhibit the varicella zoster virus (VSV) DNA polymerase enzyme. [0093] The compounds described above can also be used to treat shingles pain or pain associated with post-herpetic neuralgia, including, but not limited to, compounds of Formula (I), compounds of Formula (II), the compound of Formula (III), and compounds of Formula (IV) (including compounds of Formula (V), compounds of Formula (VI), compounds of Formula (VII), compounds of Formula (VIII), compounds of Formula (IX), compounds of Formula (X), and compounds of Formula (XI)). This includes the alternatives described above, including crystalline valomaciclovir stearate. [0094] The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time. It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test data. It is to be noted that concentrations and dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions.

[0095] In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using co-solvents, such as dimethylsulfoxide (DMSO), using surfactants, such as TWEEN®, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as prodrugs of the compounds, may also be used in formulating effective compositions. [0096] Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined. [0097] The compositions are provided for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions containing suitable quantities of the compounds or derivatives thereof. The therapeutically active compounds and derivatives thereof are, in some embodiments, formulated and administered in unit-dosage forms or multiple-dosage forms. Unit-dose forms as used herein refer to physically discrete units suitable for human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the therapeutically active compound sufficient to produce the desired therapeutic effect, in association with the required vehicle. Examples of unit- dose forms include ampules and syringes and individually packaged tablets or capsules. Unit-dose forms may be administered in fractions or multiples thereof. A multiple-dose form is a plurality of identical unit- dosage forms packaged in a single container to be administered in segregated unit-dose form. Examples of multiple-dose forms include vials, bottles of tablets or capsules or bottles of pints or gallons. Hence, multiple dose form is a multiple of unit-doses which are not segregated in packaging. [0098] Liquid administrable compositions can, for example, be prepared by dissolving, dispersing, or otherwise mixing an active compound as defined above and optional adjuvants in a vehicle, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like, for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate and other such agents. [0099] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or later editions thereof.

[0100] Dosage forms or compositions containing active ingredient in the range of 0.005% to 100% with the balance made up from one or more non-toxic carriers when the dosage forms or composition contain less than 100% active ingredient may be prepared. Methods for preparation of these compositions are known to those skilled in the art. The contemplated compositions may contain 0.001 - 100% active ingredient, in one embodiment and 0.1 -95%, in another embodiment.

[0101] In certain embodiments, the compositions are lactose-free compositions containing excipients that are well known in the art and are listed, for example, in the

U.S. Pharmacopeia (USP) 25-NF20 (2002). In general, lactose-free compositions contain active ingredients, a binder/filler, and a lubricant in compatible and acceptable amounts. Particular lactose-free dosage forms contain active ingredients, microcrystalline cellulose, pre-gelatinized starch, and magnesium stearate. [0102] Further provided are anhydrous compositions and dosage forms comprising active ingredients, since water can facilitate the degradation of some compounds. For example, the addition of water (e.g., 5%) is widely accepted in the art as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time (Carstensen, Drug Stability:

Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80). In effect, water and heat accelerate the decomposition of some compounds. Thus, the effect of water on a formulation can be of great significance since moisture and/or humidity are commonly encountered during manufacture, handling, packaging, storage, shipment, and use of formulations. [0103] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. [0104] An anhydrous composition should be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are generally packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs. [0105] Oral dosage forms are either solid, gel or liquid. The solid dosage forms are tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets which may be enteric-coated, sugar- coated or film-coated. Capsules may be hard or soft gelatin capsules, while granules and powders may be provided in non-effervescent or effervescent form with the combination of other ingredients known to those skilled in the art.

[0106] In certain embodiments, the formulations are solid dosage forms such as for example, capsules or tablets. The tablets, pills, capsules, troches and the like can contain one or more of the following ingredients, or compounds of a similar nature: a binder; a lubricant; a diluent; a glidant; a disintegrating agent; a coloring agent; a sweetening agent; a flavoring agent; a wetting agent; an enteric coating; and a film coating. Examples of binders include microcrystalline cellulose, gum tragacanth, glucose solution, acacia mucilage, gelatin solution, molasses, polvinylpyrrolidine, povidone, crospovidones, sucrose and starch paste. Lubricants include talc, starch, magnesium or calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrating agents include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar and carboxymethylcellulose. Coloring agents include, for example, any of the approved certified water soluble FD and C dyes, mixtures thereof; and water insoluble FD and C dyes suspended on alumina hydrate. Sweetening agents include sucrose, lactose, mannitol and artificial sweetening agents such as saccharin, and any number of spray dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits and synthetic blends of compounds which produce a pleasant sensation, such as, but not limited to peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol mono] aurate and polyoxyethylene laural ether. Enteric-coatings include fatty acids, fats, waxes, shellac, ammoniated shellac and cellulose acetate phthalates. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000 and cellulose acetate phthalate.

[0107] The compound, or acceptable derivative thereof, can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine. The composition may also be formulated in combination with an antacid or other such ingredient.

[0108] When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, sprinkle, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, colorings and flavors. [0109] The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action. The active ingredient is a compound or acceptable derivative thereof as described herein. Higher concentrations, up to about 98% by weight of the active ingredient may be included.

[0110] In all embodiments, tablets and capsules formulations may be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient. Thus, for example, they may be coated with a conventional enterically digestible coating, such as phenyl salicylate, waxes and cellulose acetate phthalate. [0111] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are either oil-in- water or water-in-oil. [0112] Elixirs are clear, sweetened, hydroalcoholic preparations. Vehicles used in elixirs include solvents. Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may contain a preservative. An emulsion is a two-phase system in which one liquid is dispersed in the form of small globules throughout another liquid.

Vehicles used in emulsions are non-aqueous liquids, emulsifying agents and preservatives. Suspensions use suspending agents and preservatives. Substances used in non-effervescent granules, to be reconstituted into a liquid oral dosage form, include diluents, sweeteners and wetting agents. Substances used in effervescent granules, to be reconstituted into a liquid oral dosage form, include organic acids and a source of carbon dioxide. Coloring and flavoring agents are used in all of the above dosage forms. [0113] Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate and alcohol. Examples of non-aqueous liquids utilized in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Sweetening agents include sucrose, syrups, glycerin and artificial sweetening agents such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved certified water soluble FD and C dyes, and mixtures thereof. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation.

[0114] For a solid dosage form, the solution or suspension, in for example, propylene carbonate, vegetable oils or triglycerides, is in some embodiments encapsulated in a gelatin capsule. Such solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Patent Nos. 4,328,245; 4,409,239; and

4,410,545. For a liquid dosage form, the solution, e.g., for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a liquid vehicle, e.g., water, to be easily measured for administration. [0115] Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.

Other useful formulations include those set forth in U.S. Patent Nos. RE28,81 9 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, a dialkylated mono- or poly-alkylene glycol, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol- 350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750- dimethyl ether wherein 350, 550 and 750 refer to the approximate average molecular weight of the polyethylene glycol, and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates. [0116] Other formulations include, but are not limited to, aqueous alcoholic solutions including an acetal. Alcohols used in these formulations are any water- miscible solvents having one or more hydroxyl groups, including, but not limited to, propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes such as acetaldehyde diethyl acetal.

[0117] Parenteral administration, in some embodiments characterized by injection, either subcutaneously, intramuscularly or intravenously is also contemplated herein. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. The injectables, solutions and emulsions also contain one or more excipients. Suitable excipients are, for example, water, saline, dextrose, glycerol or ethanol. In addition, if desired, the compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, stabilizers, solubility enhancers, and other such agents, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate and cyclodextrins. [0118] Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, e.g., U.S. Patent No. 3,71 0,795) is also contemplated herein. Briefly, a compound provided herein is dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The compound diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. [0119] Parenteral administration of the compositions includes intravenous, subcutaneous and intramuscular administrations. Preparations for parenteral administration include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions. The solutions may be either aqueous or non-aqueous. If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropylene glycol and mixtures thereof.

[0120] Vehicles used in parenteral preparations include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other substances. [0121] Examples of aqueous vehicles include Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral preparations packaged in multiple-dose containers which include phenols or cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citrate. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcelluose, hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifying agents include Polysorbate 80 (TWEEN® 80). A sequestering or chelating agent of metal ions include EDTA. Vehicles also include ethyl alcohol, polyethylene glycol and propylene glycol for water miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment. [0122] The concentration of active compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight and condition of the subject or animal as is known in the art.

[0123] The unit-dose parenteral preparations are packaged in an ampule, a vial or a syringe with a needle. All preparations for parenteral administration must be sterile, as is known and practiced in the art. [0124] Illustratively, intravenous or intra-arterial infusion of a sterile aqueous solution containing an active compound is an effective mode of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing an active material injected as necessary to produce the desired pharmacological effect.

[0125] Injectables are designed for local and systemic administration. In one embodiment, a therapeutically effective dosage is formulated to contain a concentration of at least about 0.1 % w/w up to about 90% w/w or more, in certain embodiments more than 1% w/w of the active compound to the treated tissue(s).

[0126] The compound may be suspended in micronized or other suitable form or may be derivatized to produce a more soluble active product or to produce a prodrug. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the condition and may be empirically determined. [0127] Active ingredients provided herein can be administered by controlled release means or by delivery devices that are well known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos.: 3,845,770; 3,91 6,899; 3,536,899; 3,598,1 23; 4,008,71 9; 5,674,533; 5,059,595; 5,591 ,767; 5,1 20,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,1 08; 5,891 ,474; 5,922,356; 5,972,891 ; 5,980,945; 5,993,855; 6,045,830;

6,087,324; 6,11 3,943; 6,1 97,350; 6,248,363; 6,264,970; 6,267,981 ; 6,376,461 ; 6,419,961 ; 6,589,548; 6,61 3,358; 6,699,500; and 6,740,634. Such dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, nanoparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein. [0128] All controlled-release products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time. Advantages of controlled-release formulations include extended activity of the drug, reduced dosage frequency, and increased subject compliance In addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and can thus affect the occurrence of side (e.g., adverse) effects. [0129] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release of other amounts of drug to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0130] In certain embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration. In some embodiments, a pump may be used (see,

Sefton, CRC Crit. RefBiorned. Eng. 14:201 ( 1 987); Buchwald et al., Surgery 88:507

(1980); Saudek et al., N Engl. J. Med. 321 :574 ( 1989). In other embodiments, polymeric materials can be used. In other embodiments, a controlled release system can be placed in proximity of the therapeutic target, i.e., thus requiring only a fraction of the systemic dose (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115-1 38 ( 1984). In some embodiments, a controlled release device is introduced into a subject in proximity of the site of inappropriate immune activation or a tumor.

Other controlled release systems are discussed in the review by Langer (Science

249:1 527-1 533 ( 1 990). The active ingredient can be dispersed in a solid inner matrix, e.g., polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene- vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate, that is surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinylacetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinylchloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, and ethylene/vinyloxyethanol copolymer, that is insoluble in body fluids. The active ingredient then diffuses through the outer polymeric membrane in a release rate controlling step. The percentage of active ingredient contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. [0131] Of interest herein are also lyophilized powders, which can be reconstituted for administration as solutions, emulsions and other mixtures. They may also be reconstituted and formulated as solids or gels. [0132] The sterile, lyophilized powder is prepared by dissolving a compound provided herein, or a pharmaceutically acceptable derivative thereof, in a suitable solvent. The solvent may contain an excipient which improves the stability or other pharmacological component of the powder or reconstituted solution, prepared from the powder. Excipients that may be used include, but are not limited to, an antioxidant, a buffer and a bulking agent. In some embodiments, the excipient is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose and other suitable agent. The solvent may contain a buffer, such as citrate, sodium or potassium phosphate or other such buffer known to those of skill in the art at about neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those of skill in the art provides the desired formulation. In one embodiment, the resulting solution will be apportioned into vials for lyophilization. Each vial will contain a single dosage or multiple dosages of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4 °C to room temperature. [0133] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The precise amount depends upon the selected compound. Such amount can be empirically determined. [0134] Topical mixtures are prepared as described for the local and systemic administration. The resulting mixture may be a solution, suspension, emulsions or the like and are formulated as creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, irrigations, sprays, suppositories, bandages, dermal patches or any other formulations suitable for topical administration. [0135] The compounds or derivatives thereof may be formulated as aerosols for topical application, such as by inhalation (see, e.g., U.S. Patent Nos. 4,044,1 26, 4,414,209, and 4,364,923, which describe aerosols for delivery of a steroid useful for treatment of inflammatory diseases, particularly asthma). These formulations for administration to the respiratory tract can be in the form of an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation will, in some embodiments, have diameters of less than 50 microns, in other embodiments less than 10 microns. [0136] The compounds may be formulated for local or topical application, such as for topical application to the skin and mucous membranes, such as in the eye, in the form of gels, creams, and lotions and for application to the eye or for intracisternal or intraspinal application. Topical administration is contemplated for transdermal delivery and also for administration to the eyes or mucosa, or for inhalation therapies. Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered. [0137] For nasal administration, the preparation may contain an esterified phosphonate compound dissolved or suspended in a liquid carrier, in particular, an aqueous carrier, for aerosol application. The carrier may contain solubilizing agents such as propylene glycol, surfactants, absorption enhancers such as lecithin or cyclodextrin, or preservatives. [0138] These solutions, particularly those intended for ophthalmic use, may be formulated as 0.01 %-1 0% isotonic solutions, pH about 5-7, with appropriate salts. Other routes of administration, such as transdermal patches, including iontophoretic and electrophoretic devices, and rectal administration, are also contemplated herein. Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those of skill in the art. For example, such patches are disclosed in U.S. Patent Nos. 6,267,983, 6,261 ,595, 6,256,533, 6,167,301 , 6,024,975, 6,01 071 5, 5,985,31 7, 5,983,1 34, 5,948,433, and 5,860,957. [0139] Dosage forms for rectal administration include, but are not limited to, rectal suppositories, capsules and tablets for systemic effect. Rectal suppositories as used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients. Substances utilized in rectal suppositories are bases or vehicles and agents to raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol) and appropriate mixtures of mono-, di- and triglycerides of fatty acids. Combinations of the various bases may be used. Agents to raise the melting point of suppositories include spermaceti and wax. Rectal suppositories may be prepared either by the compressed method or by molding. The weight of a rectal suppository, in one embodiment, is about 2 to 3 gm. Tablets and capsules for rectal administration are manufactured using the same substances and by the same methods as for formulations for oral administration. [0140] The compounds provided herein, or derivatives thereof, may also be formulated to be targeted to a particular organ, tissue, receptor, or other area of the body of the subject to be treated. Many such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein for use in the instant compositions. For non-limiting examples of targeting methods, see, e.g., U.S.

Patent Nos. 6,31 6,652, 6,274,552, 6,271 ,359, 6,253,872, 6,1 39,865, 6,1 3 1,570,

6,1 20,751 , 6,071 ,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542 and 5,709,874. Such targeting methods include, but are not limited to, the conjugation of carrier substances, such as antibodies, hormones, receptor agonists or antagonists, or receptors to antiviral compounds as described herein. As used herein, unless further defined or limited, the term "antibody" encompasses both polyclonal and monoclonal antibodies, as well as genetically engineered antibodies such as chimeric or humanized antibodies of the appropriate binding specificity. As used herein, unless further defined, the term "antibody" also encompasses antibody fragments such as sFv, Fv, Fab, Fab' and F(ab)'2 fragments. In many cases, it is preferred to use monoclonal antibodies. Receptors are well known in the art and include G-protein coupled receptors (GPCRs). G-protein coupled receptors (GPCRs) are important signal transducing receptors. The superfamily of G protein coupled receptors includes a large number of receptors. These receptors are integral membrane proteins characterized by amino acid sequences that contain seven hydrophobic domains, predicted to represent the transmembrane spanning regions of the proteins. They are found in a wide range of organisms and are involved in the transmission of signals to the interior of cells as a result of their interaction with heterotrimeric G proteins. They respond to a diverse range of agents including lipid analogues, amino acid derivatives, small molecules such as epinephrine and dopamine, and various sensory stimuli. The properties of many known GPCR are summarized in S. Watson & S. Arkinstall, "The G-Protein Linked Receptor Facts Book" (Academic Press, London, 1994), incorporated herein by this reference. GPCR receptors include, but are not limited to, acetylcholine receptors, β -adrenergic receptors, 3-adrenergic receptors, serotonin (5-hydroxytryptamine) receptors, dopamine receptors, adenosine receptors, angiotensin Type II receptors, bradykinin receptors, calcitonin receptors, calcitonin gene-related receptors, cannabinoid receptors, cholecystokinin receptors, chemokine receptors, cytokine receptors, gastrin receptors, endothelin receptors, γ - aminobutyric acid (GABA) receptors, galanin receptors, glucagon receptors, glutamate receptors, luteinizing hormone receptors, choriogonadotrophin receptors, follicle- stimulating hormone receptors, thyroid-stimulating hormone receptors, gonadotrophin- releasing hormone receptors, leukotriene receptors, Neuropeptide Y receptors, opioid receptors, parathyroid hormone receptors, platelet activating factor receptors, prostanoid (prostaglandin) receptors, somatostatin receptors, thyrotropin-releasing hormone receptors, vasopressin and oxytocin receptors. Agonists and antagonists specifically binding these receptors can be used as individual carrier substances; suitable receptors, agonists, or antagonists can be selected based on their specificity and the location of the receptors in particular cells or tissues.

[0141] In some embodiments, liposomal suspensions, including tissue-targeted liposomes, such as tumor-targeted liposomes, may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. For example, liposome formulations may be prepared as described in U.S. Patent No. 4,522,811 . Briefly, liposomes such as multilamellar vesicles (MLV's) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine

(7:3 molar ratio) on the inside of a flask. A solution of a compound provided herein in phosphate buffered saline lacking divalent cations (PBS) is added and the flask shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compound, pelleted by centrifugation, and then resuspended in PBS. [0142] The compounds or derivatives thereof may be packaged as articles of manufacture containing packaging material, a compound or pharmaceutically acceptable derivative thereof provided herein, which is effective for treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with shingles, shingles pain, or post-herpetic neuralgia, within the packaging material, and a label that indicates that the compound, derivative or composition thereof, is used for the treatment, prevention or amelioration of one or more symptoms of diseases or disorders associated with shingles, shingles pain, or post-herpetic neuralgia. [0143] The articles of manufacture provided herein can contain packaging materials. Packaging materials for use in packaging products are well known to those of skill in the art. See, e.g., U.S. Patent Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease or disorder associated with shingles, shingles pain, or post-herpetic neuralgia. [0144] Dosages

[0145] In human therapeutics, the physician will determine the dosage regimen that is most appropriate according to a preventive or curative treatment and according to the age, weight, stage of the disease and other factors specific to the subject to be treated. The compositions, in other embodiments, should provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day. Dosage unit forms are prepared, e.g., to provide from about 0.01 mg, 0.1 mg or 1 mg to about 500 mg, 1000 mg or 2000 mg, and in some embodiments, from about 10 mg to about 500 mg of the active ingredient or a combination of essential ingredients per dosage unit form. In other embodiments, the compounds may be administered at a daily dose generally in the range 0.1 mg/kg/day to 200 mg/kg/day, 0.5 mg/kg/day to 100 mg/kg/day, 10 mg/kg/day to 50 mg/kg/day or 10 mg/kg/day to 25 mg/kg/day.

[0146] In some embodiments, a method of treating shingles comprising administration of an efficacious amount of an antiviral agent according to a "front- loading" dosing regimen is provided. The "front-loading" dosing regimen comprises administration of twice the amount of the normal daily dose for 1-3 days, and optionally, followed by administration of the normal daily dose for 1-6 days. In some embodiments, the "front-loading" dosing regimen comprises BID (two times a day) administration of the unit dosage for 3 days, and optionally, followed by QD (once a day) administration of a unit dosage for 4 days.

[0147] In some embodiments, the antiviral agent is administered at a daily cumulative dose of between about 500 mg and 3000 mg, in split dosing either BID or

TID. In other embodiments, the antiviral agent is administered at a dose of between about 1.0 g QD and about 3.0 g BID. In still other embodiments, the antiviral agent is administered at a dose of between about 1.5 g and about 2.5 g BID. In still other embodiments, the antiviral agent is administered at a dose of about 2.0 g BID.

[0148] In some embodiments, the compound of Formula (II) is administered at a dose of between about 500 mg QD or BID and about 3000 mg, QD or BID. In other embodiments, the compound of Formula (II) is administered at a dose of between about

1.0 g QD or BID and about 3.0 g QD or BID. In still other embodiments, the compound of Formula (II) is administered at a dose of between about 1.5 g QD or BID and about

2.5 g QD or BID. In still other embodiments, the compound of Formula (II) is administered at a dose of about 2.0 g QD or BID or about 3.0 g QD or BID.

[0149] The amount of active ingredient in the compositions provided herein, which will be effective in the prevention or treatment of a disorder or one or more symptoms thereof, will vary with the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The frequency and dosage will also vary according to factors specific for each subject depending on the specific therapy (e.g., therapeutic or prophylactic agents) administered, the severity of the disorder, disease, or condition, the route of administration, as well as age, body weight, response, and the past medical history of the subject. [0150] Exemplary doses of a combination include milligram or microgram amounts of the active compounds per kilogram of subject or sample weight (e.g., from about 1 micrograms per kilogram to about 50 milligrams per kilogram, from about 10 micrograms per kilogram to about 30 milligrams per kilogram, from about 100 micrograms per kilogram to about 10 milligrams per kilogram, or from about 100 microgram per kilogram to about 5 milligrams per kilogram).

[0151] It may be necessary to use dosages of the active ingredients outside the ranges disclosed herein in some cases, as will be apparent to those of ordinary skill in the art. Furthermore, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with subject response. [0152] Different therapeutically effective amounts may be applicable for different diseases and conditions, as will be readily known by those of ordinary skill in the art. Similarly, amounts sufficient to prevent, manage, treat or ameliorate such disorders, but insufficient to cause, or sufficient to reduce, adverse effects associated with the composition provided herein are also encompassed by the above described dosage amounts and dose frequency schedules. Further, when a subject is administered multiple dosages of a composition provided herein, not all of the dosages need be the same. For example, the dosage administered to the subject may be increased to improve the prophylactic or therapeutic effect of the composition or it may be decreased to reduce one or more side effects that a particular subject is experiencing.

[0153] In certain embodiments, administration of the same formulation provided herein may be repeated and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months or 6 months. [0154] Combination Therapy

[0155] The compounds and compositions provided herein may also be used in combination with one or more other active ingredients. In certain embodiments, the compounds may be administered in combination, or sequentially, with another therapeutic agent to treat or prevent shingles or to prevent post herpetic neuralgia. Other therapeutic agents may include antidepressants, anticonvulsants (i.e., gabapentin or pregabalin), topical agents such as lidocaine patches or capsicoid lotion and agents known to be useful for treating neuropathic pain. Opioid analgesics may also be appropriate in many situations. Such other therapeutic agents include those known for treatment, prevention, or amelioration of one or more symptoms associated with shingles, shingles pain, or post-herpetic neuralgia. [0156] Pharmaceutical Compositions [0157] Another aspect of the invention is a pharmaceutical composition.

[0158] In one alternative, the pharmaceutical composition comprises:

( 1) a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, with the proviso that the antiviral agent is not 64 02P(0)C02H or 02P(0)CH2C02H and (2) a pharmaceutically acceptable carrier. [0159] Typically, the pharmaceutically acceptable carrier is selected from the group consisting of a binder, a lubricant, a diluent, a glidant, a disintegrating agent, a coloring agent, a sweetening agent, a flavoring agent, a wetting agent, an enteric coating, a film coating, a buffer, a preservative, an antibacterial agent, an emulsifying agent, a solubilizing agent, a wetting agent, a filler, a liquid carrier, and an antioxidant.

[0160] In another alternative, the pharmaceutical composition comprises:

( 1) a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is an antiviral agent selected from the group consisting of valomaciclovir stearate (EPB-348), octadecyloxyethyl- cidofovir (ODE-CDV, CMX-001 ), hexadecyloxypropyl-cidofovir (HDP-CDV), abacavir, adefovir, amantadine, amprenavir, arbidol, atzanavir, atripla, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emthcitabine, enfuvirtide, entecavir, entry inhibitors, antiretroviral, fomivirsen, fosamprenavir, fusion inhibitors, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, lopinavir, loviride, MK-051 8, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, synergistic enhancer, tenofovir, tenofovir disproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valavivlovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, A-5021 ([1 'S,2'R)-9[[1 '2'- bis(hydroxymethyl)cycloprop-1 '-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-l-62), 2,4-diamino-6-R43-hydroxy-2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), N-(4-chlorobenzyl)-1 -methyl-6-(4-morpholinylmethyl)-4-oxo-1 ,4-dihydro-3- quinolinecarboxamide (PNU-1 83792), 2-bromo-5,6-dichloro-1 -(beta-D- ribofuranosyl)benzimidazole (BDCRB), 1-(beta-L-ribofuranosyl)-2-isopropylamino-5,6- dichlorobenzimidazole (Maribavir, 1263W94), 3-hydroxy-2,2-dimethyl-N[4-{[(5- dimethylamino)-1 -naphthyl]-sulfonyl}-amino)phenyl}propamide (BAY 38-4766), 4-(2- amino-4-thiazolyl)phenyl derivative (BILS 179BS), N45-(aminosulfonyl)-4-methyl-1 ,3- thiazol-2-yl]-N-methyl-2-{4-(2-pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4- chlorophenyl)-3,4-dihydro-1 ,4-benzo-thiazine-2-carbonitrile-1 -oxide or 1, 1 -dioxide and 2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydronindolizine-1 -carboxamide (CMV423); and (2) a pharmaceutically acceptable carrier.

[0161] In still another alternative, the pharmaceutical composition comprises:

( 1) a therapeutically effective quantity of a compound of Formula (I): (I). wherein:

(i) Ri is hydrogen, hydroxy, mercapto, or amino;

(ii) R2 is hydrogen, hydroxy, fluoro, chloro, or amino;

(iii) R3 and R are independently selected from

amino, hydroxy, or an ether or ester residue thereof, or R3 together with R is

o

OM

wherein: M is hydrogen; and n is 1 or 2 with the proviso that when R2 is amino and R 3 and R are hydroxy, R is not hydroxy, and, in addition, when n is 1, R2 is not hydrogen; or a salt, solvate, hydrate, or mixture thereof; and (2) a pharmaceutically acceptable carrier. [0162] In still another alternative, the pharmaceutical composition comprises:

( 1) a therapeutically effective quantity of a compound of Formula (II):

wherein:

(a) in a first alternative, Ri is hydrogen, -C(O)CH(CH(CH 3)2)NH2 or

-C(O)CH(CH(CH3)CH2CH3)NH 2; R is hydrogen or -C(0)C 3-C2i saturated or monounsaturated, optionally substituted alkyl; and R3 is OH or H; or

(b) in a second alternative, R is hydrogen o -C(O)C 3-C saturated or monounsaturated, optionally substituted alkyl; R2 is hydrogen, -

C(O)CH(CH(CH 3)2)NH 2 or -C(O)CH(CH(CH 3)CH2CH3)NH2; and R3 is OH or H; or a salt, solvate, or hydrate thereof; and (2) a pharmaceutically acceptable carrier.

[0163] In this alternative, R3 can be OH. In this alternative, Ri can be -

C(O)CH(CH(CH 3)2)NH 2 or -C(O)CH(CH(CH 3)CH2CH3)NH2 and R2 can be -C(0)C 3-C2i saturated or monounsaturated, alkyl optionally substituted with up to five substituents independently selected from the group consisting of hydroxy, CrC 6 alkyl, CrC 6 alkoxy,

Ci-C 6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro. In this alternative, Ri or R can be -C(O)(Cg -Ci7) saturated or unsaturated alkyl.

[0164] In this alternative, the compound of Formula (II) can be (R)-9-[2- (stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(myristoyloxymethyl)-4-(L- valyloxy)butyl]guanine, (R)-9-[2-(oleoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2- (butyrloyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L- valyloxy)butyl]guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)- 9-[2-(dodecanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(palmitoyloxymethyl)- 4-(L-valyloxy)butyl]guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L- isoleucyloxy)butyl]guanine, (R)-9-[2-(4-acetylbutryloyloxymethyl)-4-(L- valyloxy)butyl]guanine, R-(9)-(valyloyloxymethyl)-4-(L-stearoyloxy)butyl]guanine, (R)-9- [4-(isoleucyloxymethyl)-2-(L-stearoyloxyethyl)butyl]guanine or (R)-9-[4- (isoleucyloxymethyl)-2-(L-myristoyloxymethyl)butyl]guanine. Typically, the compound of Formula (II) is (R)-9-[2-stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine. Typically, the pharmaceutical composition of claim 75 wherein the (R)-9-[2-stearoyloxymethyl)-4-(L- valyloxy)butyl]guanine is crystalline and has characteristic absorption peaks at 2-Θ angles of 22.9° +/- 0.2°, 8.6° +/- 0.2°, 9.5° +/- 0.2°, 24.3° +/- 0.2°, 20.8° +/- 0.2°, 2 .8° +/- 0.2°, 27.0° +/- 0.2°, 14.7° +/- 0.2°, 15.5° +/- 0.2°, 25.5° +/- 0.2°, and 29.9° +/- 0.2° with Cu Ka radiation in a X-ray powder diffractogram. Typically, the crystalline valomaciclovir stearate is at least 90% pure. Preferably, the crystalline valomaciclovir stearate is at least 95% pure. More preferably, the crystalline valomaciclovir stearate is at least 99% pure.

[0165] In another alternative, the pharmaceutical composition comprises:

( 1) a compound of Formula (IV), wherein the compound of Formula (IV) is selected from the group consisting of a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), and a compound of Formula (XI); and (2) a pharmaceutically acceptable carrier.

[0166] Finally, it should be noted that there are alternative ways of implementing the present invention. Accordingly, the present embodiments are to be considered as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope and equivalents of the appended claims.

[0167] All publications and patents cited herein are incorporated by reference in their entirety. [0168] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the invention. EXAMPLES [0169] The invention will now be described in greater detail by reference to the following non-limiting examples. [0170] Example 1: EPB-348 Dosed Once a Day (2q) is Non-inferior to Valacvclovir Dosed Three Times a Day (3 g) with Respect to Time to Complete Crusting [0171] A randomized, double-blind, active-controlled, multi-center, parallel-group study of valomaciclovir stearate was conducted. Patients were randomized to each of the following treatment groups: Group 1: EPB-348 1000 mg QD; Group 2 : EPB-348 2000 mg QD; Group 3 : EPB-348 3000 mg QD; Group 4 : Valacvclovir 1000 mg TID. All eligible patients were treated within 72 hours of the onset of the zoster rash for a total of 7 days and then followed until Day 28 (Week 4). Vesicle, rash, and pain assessments were performed on Days 1 through 7, and Days 10, 14, 2 1, and 28.

[0172] The mean time to complete crusting was 10.7 days in the EPB-348 2000 mg group and 11.5 days in the valacvclovir group. The 95% C I for time to complete crusting based on estimates from a Kaplan-Meier (KM) model showed non-inferiority between the EPB 348 2000 mg group and the valacvclovir group. [0173] Example 2 : EPB-348 Dosed Once Daily (3 g) is superior to Valacvclovir Dosed Three Times a Day (3 g) with Respect to Time to Complete Crusting

[0174] In the same study, exploratory analyses of the EPB-348 3000 mg group showed that the mean time to crusting in this group was 7.2 days and 17 (94.4%) patients achieved complete crusting by Day 28. The time to complete crusting in the

EPB-348 3000 mg group was statistically significantly lower than in the valacvclovir group (p=0.008). The linear trend test of time to complete crusting by Day 28, including the EPB-348 3000 mg group, was statistically significant (p=0.042). [0175] Example 3 : EPB-348 Dosed Once Daily (1, 2, and 3 g) Shows Dose- dependent Trends to Improvement Over Valacvclovir Dosed Three Times a Day (3 g) with Respect to Time to Complete Cessation of Pain at 28 Days

[0176] In the same study, patients completed a daily pain diary from Days 1 through 28. Exploratory analyses showed that: 1) 8 1 (70%) patients in the EPB-348 (1000 mg QD) group; 2) 9 1 (78%) patients in the EPB-348 (2000 mg QD) group; and 3)

15 (83%) patients in the EPB-348 (3000 mg QD) group had complete cessation of pain by study end. The valacyclovir 3000 mg group showed that 82 (75%) patients had complete cessation of pain by study end. [0177] Example 4 : EPB-348 Dosed Once Daily (1, 2, and 3 q) Shows Dose- Dependent Trends to Improvement Over Valacvclovir Dosed Three Times a Day (3 g) with Respect to Number of Patients Having Pain on Day 120 (defined as Post¬ herpetic Neuralgia, PHN)

[0178] In the same study, patients whose rash or zoster-associated pain was not resolved by the Day 28 visit continued to be followed until rash and pain resolution, up to Day 120. Exploratory analyses showed that: 1) 5 out of 1 1 5 patients in the EPB-348

(1000 mg QD) group; 2) 1 out of 117 patients in the EPB-348 (2000 mg QD) group; and

3) 0 out of 18 patients in the EPB-348 (3000 mg QD) group had pain on day 120. The valacyclovir 3000 mg group showed that 3 out of 109 patients had pain on day 120. These data indicate dose-dependent trends to improvement over valacyclovir dosed three times a day (3 g) with respect to number of patients having pain on day 120 (defined as Post-Herpetic Neuralgia, PHN). [0179] Example 5 : EPB-348 Dosed Once Daily (1, 2 g) Shows Trends to Improvement Over Valacvclovir Dosed Three Times a Day (3 g) with Respect to Time To Complete Cessation of Pain for Patients Who Had Pain on Day 28 (ZAP)

[0180] In the same study, patients > 50 years old who had any pain at day 28, the EPB-348 1000 mg and 2000 mg dosage groups exhibited trends toward reduced time to complete cessation of pain compared to valacyclovir. The mean time to complete cessation of pain for EPB-348 ( 1000 mg and 2000 mg) was shorter by 15.8 to 17.7 days compared to valacyclovir though the improvement was not statistically significant. Formally, non inferiority criteria were met for EPB-348 (2000 mg) compared to valacyclovir. Similar trends were observed in the full pool of patients 18 years old and older. Exploratory analyses showed that: 1) 5 out of 115 patients in the EPB-348 ( 1 000 mg

QD) group; 2) 1 out of 117 patients in the EPB-348 (2000 mg QD) group; and 3) 0 out of

18 patients in the EPB-348 (3000 mg QD) group had pain on day 120. The valacyclovir 3000 mg group showed that 3 out of 109 patients had pain on day 120. These data indicate dose-dependent trends to improvement over valacyclovir dosed three times a day (3 g) with respect to number of patients having pain on day 120 (defined as Post herpetic Neuralgia, PHN). [0181] Example 6 : EPB-348 dosing arms all exhibited trends toward reduced time to full crusting on day 3 compared to valacyclovir.

[0182] In the same study, those patients who received treatment at the latest time interval on day 3 (between 48-72 hours after rash onset), valacyclovir treatment was most effective when initiated within the first 48 hours with efficacy dropping off on day 3 (Mean time to complete crusting was 10.8 days (0-48h) versus 13.3 days (48-72 h) . The EPB-348 dosing arms all exhibited trends toward reduced time to full crusting on day 3 compared to valacyclovir, though these differences were not statistically significant (Mean time to complete crusting was: 1000 mg EPB-348, 12.7 days (0-48h) versus 10.8 days (48-72 h); 2000 mg EPB-348, 10.5 days (0-48h) versus 11.2 days (48-72 h); 3000 mg EPB-348, 6.8 days (0-48h) versus 8.3 days (48-72 h). ADVANTAGES OF THE INVENTION [0183] The present invention provides methods and compositions for treating shingles pain and pain associated with post-herpetic neuralgia. The methods and compositions according to the present invention are effective in treating shingles, shingles pain and pain associated with post-herpetic neuralgia, are free of side effects, and can be employed together with other therapeutic agents to treat shingles pain or pain associated with post-herpetic neuralgia. [0184] Methods according to the present invention possess industrial applicability for the preparation of a medicament for the treatment of a condition including, but not necessary limited to, shingles, shingles pain and pain associated with post-herpetic neuralgia. Compositions according to the present invention possess industrial applicability as pharmaceutical compositions with a therapeutic use. [0185] The method claims of the present invention provide specific method steps that are more than general applications of laws of nature and require that those practicing the method steps employ steps other than those conventionally known in the art, in addition to the specific applications of laws of nature recited or implied in the claims, and thus confine the scope of the claims to the specific applications recited therein. In some contexts, these claims are directed to new ways of using an existing drug.

[0186] The inventions illustratively described herein can suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the future shown and described or any portion thereof, and it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions herein disclosed can be resorted by those skilled in the art, and that such modifications and variations are considered to be within the scope of the inventions disclosed herein. The inventions have been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the scope of the generic disclosure also form part of these inventions. This includes the generic description of each invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised materials specifically resided therein.

[0187] In addition, where features or aspects of an invention are described in terms of the Markush group, those schooled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. It is also to be understood that the above description is intended to be illustrative and not restrictive. Many embodiments will be apparent to those of in the art upon reviewing the above description. The scope of the invention should therefore, be determined not with reference to the above description, but should instead be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. The disclosures of all articles and references, including patent publications, are incorporated herein by reference. What is claimed is:

1. A method of treating or preventing shingles in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, with the proviso that the antiviral agent is not 02P(0)C02H or 02P(0)CH2C02H

2 . A method of treating shingles in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is an antiviral agent selected from the group consisting of valomaciclovir stearate (EPB-348), octadecyloxyethyl-cidofovir (ODE-CDV, CMX-001 ), hexadecyloxypropyl-cidofovir (HDP- CDV), abacavir, adefovir, amantadine, amprenavir, arbidol, atzanavir, atripla, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, entry inhibitors, antiretroviral, fomivirsen, fosamprenavir, fusion inhibitors, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, lopinavir, loviride, MK-051 8, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, synergistic enhancer, tenofovir, tenofovir disproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valavivlovir, vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir, zidovudine, A-5021 ([1 'S,2'R)-9[[1 '2'- bis(hydroxymethyl)cycloprop-1 '-yl]-methyl]guanine]), cyclopropavir (CPV, ZSM-l-62), 2,4-diamino-6-R43-hydroxy-2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), N-(4-chlorobenzyl)-1 -methyl-6-(4-morpholinylmethyl)-4-oxo-1 ,4-dihydro-3- quinolinecarboxamide (PNU-1 83792), 2-bromo-5,6-dichloro-1 -(beta-D- ribofuranosyl)benzimidazole (BDCRB), 1-(beta-L-ribofuranosyl)-2-isopropylamino-5,6- dichlorobenzimidazole (Maribavir, 1263W94), 3-hydroxy-2,2-dimethyl-N[4-{ [(5- dimethylamino)-1 - naphthyl]-sulfonyl}-amino)phenyl}propamide (BAY 38-4766), 4-(2- amino-4- thiazolyl)phenyl derivative (BILS 179BS), N45-(aminosulfonyl)-4-methyl-1 ,3- thiazol-2-yl]-N-methyl-2-{4-(2-pyridinyl)phenyl}acetamide (BAY 57-1293), 2H-3-(4- chlorophenyl)-3,4-dihydro-1 ,4-benzo-thiazine-2-carbonitrile-1 -oxide or 1, 1 -dioxide and 2-chloro-3-pyridin-3-yl-5,6,7,8-tetrahydronindolizine-1 -carboxamide (CMV423).

3 . A method of treating shingles in a subject comprising administering to a subject in need thereof a therapeutically effective quantity of a compound of Formula (I):

(I) wherein:

(i) R is hydrogen, hydroxy, mercapto, or amino; R2 is hydrogen, hydroxy, fluoro, chloro, or amino

R3 and R are independently selected from

amino, hydroxy, or an ether or ester residue thereof, or R3 together with R is

O

p .

OM

wherein: M is hydrogen; and n is 1 or 2 with the proviso that when R2 is amino and R3 and R are hydroxy, R is not hydroxy, and, in addition, when n is 1, R2 is not hydrogen; or a salt, solvate, hydrate, or mixture thereof.

4 . A method of treating shingles in a subject comprising administering to a subject in need thereof a therapeutically effective quantity of a compound of Formula (II):

2 wherein:

( 1) in a first alternative, R is hydrogen, -C(O)CH(CH(CH 3)2)NH2 or -

C(O)CH(CH(CH3)CH 2CH3)NH2; R is hydrogen or -C(0)C 3-C2i saturated or monounsaturated, optionally substituted alkyl; and R 3 is OH or H; or

(2) in a second alternative, R is hydrogen o -C(O)C 3-C saturated or monounsaturated, optionally substituted alkyl; R2 is hydrogen, -C(O)CH(CH(CH 3)2)NH or -C(O)CH(CH(CH 3)CH 2CH3)NH 2; and R3 is OH or H; or a salt, solvate, or hydrate thereof.

5 . The method of claim 4 wherein R3 is OH.

6 . The method of claim 4 wherein Ri is -C(O)CH(CH(CH 3)2)NH2 or - )CH CH )NH is -C C(O)CH(CH(CH 3 2 3 2 and R2 -C(O)C 3 2 saturated or monounsaturated, alkyl optionally substituted with up to five substituents independently selected from the group consisting of hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro.

7 . The method of claim 4 wherein or R are -C(O)(C 9-Ci 7) saturated or unsaturated alkyl.

8 . The method of claim 4 wherein the compound of Formula (II) is (R)- 9-[2-(stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(myristoyloxymethyl)-4-(L- valyloxy)butyl]guanine, (R)-9-[2-(oleoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2- (butyrloyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L- valyloxy)butyl]guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)- 9-[2-(dodecanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(palmitoyloxymethyl)- 4-(L-valyloxy)butyl]guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L- isoleucyloxy)butyl]guanine, (R)-9-[2-(4-acetylbutryloyloxymethyl)-4-(L- valyloxy)butyl]guanine, R-(9)-(valyloyloxymethyl)-4-(L-stearoyloxy)butyl]guanine, (R)-9- [4-(isoleucyloxymethyl)-2-(L-stearoyloxyethyl)butyl]guanine or (R)-9-[4- (isoleucyloxymethyl)-2-(L-myristoyloxymethyl)butyl]guanine.

9 . The method of claim 4 wherein the compound of Formula (II) is (R)- 9-[2-stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine.

10 . The method of claim 4 wherein the compound of Formula (II) is administered at a dose of between about 500 mg QD and about 3000 mg QD.

1 1 . The method of claim 4 wherein the compound of Formula (II) is administered at a dose of between about 1.0 g QD and about 3.0 g QD.

12 . The method of claim 4 wherein the compound of Formula (II) is administered at a dose of between about 1.5 g and about 2.5 g QD.

13 . The method of claim 4 wherein the compound of Formula (II) is administered at a dose of about 2.0 g QD or about 3.0 g QD.

14. The method of claim 4 wherein the compound of Formula (II) is first administered 2 days after the appearance of skin rash.

15 . The method of claim 4 wherein the compound of Formula (II) is first administered 3 days after the appearance of skin rash.

16 . The method of claim 4 wherein the compound of Formula (II) is first administered 5 days after the appearance of skin rash.

17 . The method of claim 4 wherein the compound of Formula (II) is first administered more than 5 days after the appearance of skin rash. 18 . The method of claim 17 wherein the compound of Formula (II) is (R)-9-[2-stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine.

19 . The method of claim 4 wherein the subject is greater than about 60 years of age.

20. The method of claim 19 wherein the compound of Formula (II) is first administered 2 days after the appearance of skin rash.

2 1 . The method of claim 19 wherein the compound of Formula (II) is first administered 3 days after the appearance of skin rash.

22. The method of claim 19 wherein the compound of Formula (II) is first administered more than 3 days after the appearance of skin rash.

23. The method of claim 19 wherein the compound of Formula (II) is administered at a dose of about 2.0 g QD or about 3.0 g QD.

24. The method of claim 19 wherein the compound of Formula (II) is (R)-9-[2-stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine.

25. The method of claim 4 wherein the time to full crusting is about 1 1 days when the compound of Formula (II) is administered at a dose of about 2.0 g QD.

26. The method of claim 4 wherein the time to full crusting is about 7 days when the compound of Formula (II) is administered at a dose of about 3.0 g QD.

27. A method of treating post-herpetic neuralgia comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (II): wherein:

( 1) in a first alternative, R is hydrogen, -C(O)CH(CH(CH 3)2)NH2 or - CH3 )NH is hydrogen o -C saturated or C(O)CH(CH(CH3)CH 2 2; R2 -C(O)C 3 2 1 monounsaturated, optionally substituted alkyl; and R 3 is OH or H; or

(2) in a second alternative, Ri is hydrogen o -C(O)C3-C2i saturated or monounsaturated, optionally substituted alkyl; R2 is hydrogen, -C(O)CH(CH(CH 3)2)NH or -C(O)CH(CH(CH 3)CH 2CH3)NH 2; and R3 is OH or H; or a salt, solvate, or hydrate thereof.

28. The method of claim 27 wherein R3 is OH.

29. The method of claim 27 wherein Ri is -C(O)CH(CH(CH 3)2)NH2 or -

C(O)CH(CH(CH3)CH2CH3)NH2 and R2 is -C(0)C 3-C2i saturated or monounsaturated, alkyl optionally substituted with up to five substituents independently selected from the group consisting of hydroxy, CrC 6 alkyl, CrC 6 alkoxy, CrC 6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro.

30. The method of claim 27 wherein R or R are -C(O)(Cg-Ci7) saturated or unsaturated alkyl.

3 1 . The method of claim 27 wherein the compound of Formula (I) is (R)-9-[2-(stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(myristoyloxymethyl)- 4-(L-valyloxy)butyl]guanine, (R)-9-[2-(oleoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)- 9-[2-(butyrloyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(decanoyloxymethyl)-4- (L-valyloxy)butyl]guanine, (R)-9-[2-(docosanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(dodecanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2- (palmitoyloxynnethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(decanoyloxymethyl)-4-(L- isoleucyloxy)butyl]guanine, (R)-9-[2-(4-acetylbutryloyloxymethyl)-4-(L- valyloxy)butyl]guanine, R-(9)-(valyloyloxymethyl)-4-(L-stearoyloxy)butyl]guanine, (R)-9- [4-(isoleucyloxymethyl)-2-(L-stearoyloxyethyl)butyl]guanine or (R)-9-[4- (isoleucyloxymethyl)-2-(L-myristoyloxymethyl)butyl]guanine.

32. The method of claim 27 wherein the compound of Formula (II) is (R)-9-[2-stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine.

33. The method of claim 27 wherein the compound of Formula (II) is administered at a dose of between about 500 mg QD and about 3000 mg QD.

34. The method of claim 27 wherein the compound of Formula (II) is administered at a dose of between about 1.0 g QD and about 3.0 g QD.

35. The method of claim 27 wherein the compound of Formula (II) is administered at a dose of between about 1.5 g and about 2.5 g QD.

36. The method of claim 27 wherein the compound of Formula (II) is administered at a dose of about 2.0 g QD or about 3.0 g QD.

37. The method of claim 27 wherein the pain is present about 28 days after the appearance of skin rash.

38. The method of claim 27 wherein the compound of Formula (II) is administered at a dose of about 2.0 g QD. 39. The method of claim 27 wherein the pain is present about 28 days after the appearance of skin rash and the compound of Formula (II) is administered at a dose of about 2.0 g QD.

40. The method of claim 27 wherein the pain is resolved at about 33 days.

4 1. The method of claim 27 wherein the compound of Formula (II) is administered at a dose of about 2.0 g QD and the pain is resolved at about 33 days.

42. A method of treating shingles in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is valomaciclovir stearate (Formula (III)):

(III).

43. A method of treating shingles in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is crystalline valomaciclovir stearate having characteristic absorption peaks at 2Θ angles of 22.9° +/-

0.2°, 18.6° +/- 0.2°, 19.5° +/- 0.2°, 24.3° +/- 0.2°, 20.8° +/- 0.2°, 2 1.8° +/- 0.2°, 27.0° +/- 0.2°, 14.7° +/- 0.2°, 15.5° +/- 0.2°, 25.5° +/- 0.2°, and 29.9° +/- 0.2° with Cu Ka radiation in a X-ray powder diffractogram. 44. The method of claim 43 wherein the crystalline valomaciclovir stearate is at least 90% pure.

45. The method of claim 44 wherein the crystalline valomaciclovir stearate is at least 95% pure.

46. The method of claim 45 wherein the crystalline valomaciclovir stearate is at least 99% pure.

47. A method of treating shingles in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is a compound of Formula (IV):

wherein, in Formula (IV), the antiviral compound is selected from the group consisting of:

( 1) the compound wherein R is H and R2 is H, and the compound is (R)- 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V)) (V); 2 (2) the compound wherein R is P(O)(OH)2 and R is H, and the compound is H2G-monophosphate (Formula (VI))

2 (3) the compound wherein R is P(O)(OH)-O-P(O)(OH) 2 and R is H, and the compound is H2G-diphosphate (Formula (VII))

(Vll); 1 (4) the compound wherein R is P(O)(OH)-O-P(O)(OH)-O-P(O)(OH) 2 and R2 is H, and the compound is H2G-triphosphate (Formula (VIII)) (VIII); 2 (5) the compound wherein R is H and R is P(O)(OH)2 (Formula (IX)

(ix); 2 (6) the compound wherein R is H and R is P(O)(OH)-O-P(O)(OH) 2 (Formula (X)); 88 48. A method of treating shingles in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is valomaciclovir stearate (EPB-348) or another prodrug of H2G and which upon administration is converted to a compound selected from the group consisting of (R)-9-[4-hydroxy-2- (hydroxymethyl)butyl]guanine (H2G; Formula (V)), H2G-monophosphate (Formula (VI)), H2G-diphosphate (Formula (VII), H2G-triphosphate (Formula (VIII), the compound of Formula (IX), the compound of Formula (X), and the compound of Formula (XI).

49. The method of claim 48 wherein the antiviral agent or the salt, solvate, or hydrate thereof inhibits the varicella zoster virus (VZV) DNA polymerase enzyme.

50. A method of treating shingles pain in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is valomaciclovir stearate (Formula (III)):

5 1 . A method of treating shingles pain in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is crystalline valomaciclovir stearate having characteristic absorption peaks at 2Θ angles of 22.9° +/- 0.2°, 8.6° +/- 0.2°, 9.5° +/- 0.2°, 24.3° +/- 0.2°, 20.8° +/- 0.2°, 2 .8° +/- 0.2°, 27.0° +/- 0.2°, 14.7° +/- 0.2°, 15.5° +/- 0.2°, 25.5° +/- 0.2°, and 29.9° +/- 0.2° with

Cu Ka radiation in a X-ray powder diffractogram.

52. The method of claim 5 1 wherein the crystalline valomaciclovir stearate is at least 90% pure.

53. The method of claim 52 wherein the crystalline valomaciclovir stearate is at least 95% pure.

54. The method of claim 53 wherein the crystalline valomaciclovir stearate is at least 99% pure.

55. A method of treating shingles pain in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is a compound of Formula (IV):

wherein, in Formula (IV), the antiviral compound is selected from the group consisting of:

( 1) the compound wherein R is H and R2 is H, and the compound is (R)- 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V)) (V); 2 (2) the compound wherein R is P(O)(OH)2 and R is H, and the compound is H2G-monophosphate (Formula (VI))

2 (3) the compound wherein R is P(O)(OH)-O-P(O)(OH) 2 and R is H, and the compound is H2G-diphosphate (Formula (VII))

(Vll); 1 (4) the compound wherein R is P(O)(OH)-O-P(O)(OH)-O-P(O)(OH) 2 and R2 is H, and the compound is H2G-triphosphate (Formula (VIII)) (VIII); 2 (5) the compound wherein R is H and R is P(O)(OH)2 (Formula (IX)

(ix); 2 (6) the compound wherein R is H and R is P(O)(OH)-O-P(O)(OH) 2 (Formula (X)); 93 56. A method of treating shingles pain in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is valomaciclovir stearate (EPB-348) or another prodrug of H2G and which upon administration is converted to a compound selected from the group consisting of (R)-9- [4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V)), H2G-monophosphate (Formula (VI)), H2G-diphosphate (Formula (VII), H2G-triphosphate (Formula (VIII), the compound of Formula (IX), the compound of Formula (X), and the compound of Formula (XI).

57. The method of claim 53 wherein the antiviral agent or the salt, solvate, or hydrate thereof inhibits the varicella zoster virus (VSV) DNA polymerase enzyme.

58. A method of treating pain associated with post-herpetic neuralgia in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is valomaciclovir stearate (Formula (III)):

(III).

59. A method of treating pain associated with post-herpetic neuralgia in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is crystalline valomaciclovir stearate having characteristic absorption peaks at 2Θ angles of 22.9° +/- 0.2°, 8.6° +/- 0.2°, 9.5° +/- 0.2°, 24.3° +/- 0.2°, 20.8°

+/- 0.2°, 2 .8° +/- 0.2°, 27.0° +/- 0.2°, 14.7° +/- 0.2°, 5.5° +/- 0.2°, 25.5° +/- 0.2°, and

29.9° +/- 0.2° with Cu Ka radiation in a X-ray powder diffractogram.

60. The method of claim 59 wherein the crystalline valomaciclovir stearate is at least 90% pure.

6 1 . The method of claim 60 wherein the crystalline valomaciclovir stearate is at least 95% pure.

62. The method of claim 6 1 wherein the crystalline valomaciclovir stearate is at least 99% pure.

63. A method of treating pain associated with post-herpetic neuralgia in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is a compound of Formula (IV):

wherein, in Formula (IV), the antiviral compound is selected from the group consisting of:

( 1) the compound wherein R is H and R2 is H, and the compound is (R)- 9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V)) (V); 2 (2) the compound wherein R is P(O)(OH)2 and R is H, and the compound is H2G-monophosphate (Formula (VI))

2 (3) the compound wherein R is P(O)(OH)-O-P(O)(OH) 2 and R is H, and the compound is H2G-diphosphate (Formula (VII))

(Vll); 1 (4) the compound wherein R is P(O)(OH)-O-P(O)(OH)-O-P(O)(OH) 2 and R2 is H, and the compound is H2G-triphosphate (Formula (VIII)) (VIII); 2 (5) the compound wherein R is H and R is P(O)(OH)2 (Formula (IX)

(ix); 2 (6) the compound wherein R is H and R is P(O)(OH)-O-P(O)(OH) 2 (Formula (X)); 98 64. A method of treating pain associated with post-herpetic neuralgia in a subject comprising administering to the subject in need thereof a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is valomaciclovir stearate (EPB-348) or another prodrug of H2G and which upon administration is converted to a compound selected from the group consisting of (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V)), H2G-monophosphate (Formula (VI)), H2G-diphosphate (Formula (VII), H2G- triphosphate (Formula (VIII), the compound of Formula (IX), the compound of Formula (X), and the compound of Formula (XI).

65. The method of claim 64 wherein the antiviral agent or the salt, solvate, or hydrate thereof inhibits the varicella zoster virus (VSV) DNA polymerase enzyme.

66. A pharmaceutical composition comprising: (a) a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, with the proviso that the antiviral agent is not 00 02P(0)C02H or 02P(0)CH2C02H and (b) a pharmaceutically acceptable carrier.

67. The pharmaceutical composition of claim 66 wherein the pharmaceutically acceptable carrier is selected from the group consisting of a binder, a lubricant, a diluent, a glidant, a disintegrating agent, a coloring agent, a sweetening agent, a flavoring agent, a wetting agent, an enteric coating, a film coating, a buffer, a preservative, an antibacterial agent, an emulsifying agent, a solubilizing agent, a wetting agent, a filler, a liquid carrier, and an antioxidant.

68. A pharmaceutical composition comprising: (a) a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is an antiviral agent selected from the group consisting of valomaciclovir (EPB-348), octadecyloxyethyl-cidofovir

(ODE-CDV, CMX-001 ), hexadecyloxypropyl-cidofovir (HDP-CDV), abacavir, adefovir, amantadine, amprenavir, arbidol, atzanavir, atripla, combivir, darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz, emtricitabine, enfuvirtide, entecavir, entry inhibitors, antiretroviral, fomivirsen, fosamprenavir, fusion inhibitors, gardasil, ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine, integrase inhibitor, interferon type III, interferon type II, interferon type I, interferon, lamivudine, lopinavir, lopinavir, loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine, nexavir, nucleoside analogues, oseltamivir, peramivir, pleconaril, podophyllotoxin, protease inhibitors, reverse transcriptase inhibitors, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, synergistic enhancer, tenofovir, tenofovir disproxil, tipranavir, trifluridine, trizivir, tromantadine, truvada, valavivlovir, vicriviroc, vidarabine, viramidine, zaicitabine, zanamivir, zidovudine, A-5021 ([1 'S,2'R)-9[[1 '2'-bis(hydroxymethyl)cycloprop-1 '-yl]- methyl]guanine]), cyclopropavir (CPV, ZSM-l-62), 2,4-diamino-6-R43-hydroxy- 2(phosphonomethoxy)propoxy]-pyrimidine (HPMPO-DaPy), N-(4-chlorobenzyl)-1 - methyl-6-(4-morpholinylmethyl)-4-oxo-1 ,4-dihydro-3-quinolinecarboxamide (PNU- 183792), 2-bromo-5,6-dichloro-1 -(beta-D-ribofuranosyl)benzimidazole (BDCRB), 1- (beta-L-ribofuranosyl)-2-isopropylamino-5,6-dichlorobenzimidazole (Maribavir, 1263W94), 3-hydroxy-2,2-dimethyl-N[4-{ [(5-dimethylamino)-1 - naphthyl]-sulfonyl}- amino)phenyl}propamide (BAY 38-4766), 4-(2-amino-4- thiazolyl)phenyl derivative (BILS 179BS), N45-(aminosulfonyl)-4-methyl-1 ,3- thiazol-2-yl]-N-methyl-2-{4-(2- pyridinyl)phenyl}acetamide (BAY 57-1 293), 2H-3-(4-chlorophenyl)-3,4-dihydro-1 ,4- benzo-thiazine-2-carbonitrile-1 -oxide or 1, 1 -dioxide and 2-chloro-3-pyridin-3-yl-5, 6,7,8- tetrahydronindolizine-1 -carboxamide (CMV423); and (b) a pharmaceutically acceptable carrier.

69. The pharmaceutical composition of claim 68 wherein the pharmaceutically acceptable carrier is selected from the group consisting of a binder, a lubricant, a diluent, a glidant, a disintegrating agent, a coloring agent, a sweetening agent, a flavoring agent, a wetting agent, an enteric coating, a film coating, a buffer, a preservative, an antibacterial agent, an emulsifying agent, a solubilizing agent, a wetting agent, a filler, a liquid carrier, and an antioxidant.

70. A pharmaceutical composition comprising: (a) a therapeutically effective quantity of a compound of Formula (I):

(i) R is hydrogen, hydroxy, mercapto, or amino;

(ii) R2 is hydrogen, hydroxy, fluoro, chloro, or amino;

(iii) R 3 and R4 are independently selected from

amino, hydroxy, or an ether or ester residue thereof, or R3 together with R is O

P ~ —

OM

wherein: M is hydrogen; and n is 1 or 2 with the proviso that when R2 is amino and R 3 and R are hydroxy, R is not hydroxy, and, in addition, when n is 1, R2 is not hydrogen; or a salt, solvate, hydrate, or mixture thereof; and (b) a pharmaceutically acceptable carrier.

7 1 . The pharmaceutical composition of claim 70 wherein the pharmaceutically acceptable carrier is selected from the group consisting of a binder, a lubricant, a diluent, a glidant, a disintegrating agent, a coloring agent, a sweetening agent, a flavoring agent, a wetting agent, an enteric coating, a film coating, a buffer, a preservative, an antibacterial agent, an emulsifying agent, a solubilizing agent, a wetting agent, a filler, a liquid carrier, and an antioxidant.

72. A pharmaceutical composition comprising: (a) a therapeutically effective quantity of a compound of Formula (II):

wherein: ( 1) in a first alternative, R is hydrogen, -C(O)CH(CH(CH 3)2)NH2 or CH3)NH is -C(O)CH(CH(CH3)CH 2 2; R2 hydrogen o -C(O)C 3-C2 1 saturated or monounsaturated, optionally substituted alkyl; and R 3 is OH or H; or

(2) in a second alternative, Ri is hydrogen o -C(O)C3-C 2i saturated or monounsaturated, optionally substituted alkyl; R2 is hydrogen, -

C(O)CH(CH(CH 3)2)NH 2 or -C(O)CH(CH(CH 3)CH2CH3)NH2; and R3 is OH or H; or a salt, solvate, or hydrate thereof; and (b) a pharmaceutically acceptable carrier.

73. The pharmaceutical composition of claim 72 wherein the pharmaceutically acceptable carrier is selected from the group consisting of a binder, a lubricant, a diluent, a glidant, a disintegrating agent, a coloring agent, a sweetening agent, a flavoring agent, a wetting agent, an enteric coating, a film coating, a buffer, a preservative, an antibacterial agent, an emulsifying agent, a solubilizing agent, a wetting agent, a filler, a liquid carrier, and an antioxidant.

74. The pharmaceutical composition of claim 72 wherein R3 is OH.

75. The pharmaceutical composition of claim 72 wherein R is -

C(O)CH(CH(CH 3)2)NH 2 or -C(O)CH(CH(CH 3)CH2CH3)NH2 and R2 is -C(0)C 3-C2i saturated or monounsaturated, alkyl optionally substituted with up to five substituents independently selected from the group consisting of hydroxy, CrC 6 alkyl, CrC 6 alkoxy, C1-C6 alkanoyl, amino, halo, cyano, azido, oxo, mercapto and nitro.

76. The pharmaceutical composition of claim 72 wherein or R are -

C(O)(C 9-Ci 7) saturated or unsaturated alkyl.

77. The pharmaceutical composition of claim 72 wherein the compound of Formula (II) is (R)-9-[2-(stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2- (myristoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(oleoyloxymethyl)-4-(L- valyloxy)butyl]guanine, (R)-9-[2-(butyrloyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9- [2-(decanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(docosanoyloxymethyl)-4- (L-valyloxy)butyl]guanine, (R)-9-[2-(dodecanoyloxymethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2-(palmitoyloxynnethyl)-4-(L-valyloxy)butyl]guanine, (R)-9-[2- (decanoyloxymethyl)-4-(L-isoleucyloxy)butyl]guanine, (R)-9-[2-(4- acetylbutryloyloxymethyl)-4-(L-valyloxy)butyl]guanine, R-(9)-(valyloyloxymethyl)-4-(L- stearoyloxy)butyl]guanine, (R)-9-[4-(isoleucyloxymethyl)-2-(L- stearoyloxyethyl)butyl]guanine or (R)-9-[4-(isoleucyloxymethyl)-2-(L- myristoyloxynnethyl)butyl]guanine.

78. The pharmaceutical composition of claim 72 wherein the compound of Formula (II) is (R)-9-[2-stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine.

79. The pharmaceutical composition of claim 78 wherein the (R)-9-[2- stearoyloxymethyl)-4-(L-valyloxy)butyl]guanine is crystalline and has characteristic absorption peaks at 2Θ angles of 22.9° +/- 0.2°, 8.6° +/- 0.2°, 9.5° +/- 0.2°, 24.3° +/-

0.2°, 20.8° +/- 0.2°, 2 .8° +/- 0.2°, 27.0° +/- 0.2°, 14.7° +/- 0.2°, 15.5° +/- 0.2°, 25.5° +/-

0.2°, and 29.9° +/- 0.2° with Cu Ka radiation in a X-ray powder diffractogram.

80. The pharmaceutical composition of claim 79 wherein the crystalline valomaciclovir stearate is at least 90% pure.

8 1 . The pharmaceutical composition of claim 80 wherein the crystalline valomaciclovir stearate is at least 95% pure.

82. The pharmaceutical composition of claim 8 1 wherein the crystalline valomaciclovir stearate is at least 99% pure.

83. A pharmaceutical composition comprising: (a) a therapeutically effective quantity of an antiviral agent or a salt, solvate, or hydrate thereof, wherein the antiviral agent is a compound of Formula (IV):

(IV) wherein, in Formula (IV), the antiviral compound is selected from the group consisting of:

( 1) the compound wherein R is H and R2 is H, and the compound is (R)-9-[4-hydroxy-2-(hydroxymethyl)butyl]guanine (H2G; Formula (V))

(V); 2 (2) the compound wherein R is P(O)(OH)2 and R is H, and the compound is H2G-monophosphate (Formula (VI)) (VI); 2 (3) the compound wherein R is P(O)(OH)-O-P(O)(OH) 2 and R is H, and the compound is H2G-diphosphate (Formula (VII))

(4) the compound wherein R is P(O)(OH)-O-P(O)(OH)-O- 2 P(O)(OH)2 and R is H, and the compound is H2G-triphosphate (Formula (VIII))

1 2 (5) the compound wherein R is H and R is P(O)(OH)2 (Formula (ix); (6) the compound wherein R is H and R2 is P(O)(OH)-O-

P(O)(OH)2 (Formula (X));

(X); and

(7) the compound wherein R is H and R2 is P(O)(OH)-O-

P(O)(OH)-O-P(O)(OH) 2 (Formula (XI) (XI); and (b) a pharmaceutically acceptable carrier.

84. The pharmaceutical composition of claim 83 wherein the pharmaceutically acceptable carrier is selected from the group consisting of a binder, a lubricant, a diluent, a glidant, a disintegrating agent, a coloring agent, a sweetening agent, a flavoring agent, a wetting agent, an enteric coating, a film coating, a buffer, a preservative, an antibacterial agent, an emulsifying agent, a solubilizing agent, a wetting agent, a filler, a liquid carrier, and an antioxidant.