WO2013008182A1

WO2013008182A1 - Prodrugs of gaba analogs

Info

Publication number: WO2013008182A1
Application number: PCT/IB2012/053529
Authority: WO
Inventors: Mahesh Kandula
Original assignee: Mahesh Kandula
Priority date: 2011-07-10
Filing date: 2012-07-10
Publication date: 2013-01-17

Abstract

The disclosures herein provide compounds of formula Ϊ, formula II, formula 111 and formula IV or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers, and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for oral administration, transdermal administration, transmucosal, syrups, topical, extended or sustained release, or injection. Such compositions may be used to treatment of neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain, epilepsy, restless leg syndrome, and other diseases related sub-chronic and chronic pain or its associated complications.

Description

PRODRUGS OF GABA ANALOGS

PRIORITY

[0001] This application claims priority to United States Provisional Application No. 61512898, filed on 28* July; 201 1 and United States Non-Provisional Application No. 13545035, filed on 10* of July, 2012. The entire disclosures of those applications are relied on and incorporated into the application by reference.

FIELD O VE iQN

[0002] This disclosure generally relates to compounds and compositions for the treatment of neuropathic pain and other neurological disorders. More particularly, this invention relates to treating subjects with a pharmaceutically acceptable dose of compounds, crystals, esters, salts, hydrates, enaniioniers, stereoisomers, prodrugs, or mixtures thereof.

BAC GROL D

[0003] Neuropathic pain usually responds poorly to the standard treatments described in the World Health Organization's analgesics ladder, such as non-steroidal antiinflammatory drugs (NSAIDs) and opioids. Antidepressants have been shown to be of benefit in diabetic neuropathy, with the best effects achieved with tricyclic antidepressants (TCAs). However, the adverse events of TCAs are frequently severe enough to lead to drug withdrawal.

j0004| The gamma - aminohutyric acid (GABA) pathwa forms a major inhibitory¹ neurotransmitter system in the CJNS targeted for the treatment of DP . The antiepileptic gabapentin became the first agent for the treatment of all neuropathic pain conditions, based on evidence from large randomized trials in two types of neuropathic pain.

[0005] Gabapentin is widely used for neuropathic pain due to its effectiveness and relatively fewer side effects than TCA and other anticonvulsants. Gabapentin produces analgesia via binding to the ot2-6 site of L-rype voltage gated calcium channels and decreasing calcium influx. Gabapentin is usually well tolerated with slow titration. Moreover, it usually takes weeks of titration to reach the maximal effective dose and a dosing of 3/day is often necessary. Like gabapentin, pregabalin also acts by binding to the α2-δ subunit of calcium channels. As demonstrated in four randomized placebo control trials, pregabaiin (300-600 rag/day) is significantly more effective in alleviating DPN than placebo. Unlike gabapentin, pregabaiin has better Gl absorption and can be administered twice per day. Its linear pharmacokinetics provide a rapid (b2 weeks) onset of maxima! pain relief

j^'0006| Gabapentin bioavailability is dose-dependent, decreasing from an average of aboui 60% at a 300-rog dose to about 35% or less at doses used to treat neuropathic pain. The underlying mechanism of this dose dependence is thought to be saturation of gabapentin absorption from the intestine. Gabapentin is absorbed by a low-capacity solute transporter localized in the upper small intestine, possibly an L-type amino acid transporter. The absorption pathway for gabapentin in human intestine can be saturated at doses that are used to treat neuropathic pain. As a result, plasma levels of gabapentin are unpredictable and may not reach therapeutically useful levels in some patients.

[0007] it has been reported recently that exposure to gabapentin at high oral doses increased in a linear manner. However, this study was based on limited data from less than 10 subjects, only four of which reached the highest dose of 4800 rag/day. Several larger clinical studies have clearly demonstrated the lack of dose proportionality for oral gabapentin; Neurontin Summary Basis of Approval, DA 20-235, U.S. Food And Drug Administration).

[0008] The large interpatient differences in plasma gabapentin exposure observed clinically are likel the result of highly variable intestinal expression of the gabapentin transporter between individuals and the narrow localization of the transporter in the small intestine. A subset of patients appears to have limited abilit to absorb gabapentin, possibly due to a lower abundance of the transporter in their intestines.

[0009] Managing acute pathology of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment of neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain

^■7 |0010] The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the effects of the conditions such as neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain.

|0 11j The invention herein provides compositions comprising of formula ! or pharmaceutical acceptable salts thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula i. or intermediates thereof and one or more of pharmaceutically acceptable carriers., vehicles or diluents. These compositions may be used in the treatment of neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pai .

For nulla I

Wherein

R^f is independently selected from the group consisting of hydrogen, methyl amine, carboxyl. hydroxy I, (S)-butane-l,2-dioi, 2-hydroxy aeetaxnide, cycohexy! methyl ether, butoxy, propoxy. thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acy!.

R² each independently represents

each a is independently 5 or 6;

each b is independently 2 or 3;

|00121 in another aspect, compounds of formula II are described :

Formula Π and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein

R* is independently selected from the group consisting of hydrogen, methyl, amine, carboxyl, hydroxyl, (S)-butane-1.,2-dioi, 2-hydroxy acetamide, cvcohexyl methyl ether, butoxy, ropoxy, thiol, alkyl, alky! thiol, acetyl thiol, disulfide, acyl.

R² each independently represents

each b is independently 2 or 3; 0013J In another aspect, compounds of formula III are described:

Formula III

and phanTsaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

R¹ is independently selected from the group consisting of hydrogen, methyl, amine, carboxyl, hydroxyl, (S)-butane- 1 ,2-diol, 2-hydroxy acetamide, cycohexy! methyl ether, butoxy, propoxy, thiol, alkyl, alky! thiol, acetyl thiol, disulfide, acyl,

2 each i independently represents

each a is independently 5 or 6;

each b is independently 2 or 3;

|001 | In another aspect, compounds of formula IV are described;

Formuia IV

and pharmaceutically acceptable salts, hydrates, solvates, prodmgs, enanfcomers, and stereoi somer s thereof;

l is independently selected from the group consisting of hydrogen, methyl, amine, carboxyi, hydroxyl, (S)-butane-l ,2-diot, 2-hydroxy acetaroide, cycohexyl methyl ether, biitoxy, propoxy, thiol, alkyl, a!kyl thiol, acetyl thiol, disulfide, acyS,

R² each independently represents

each a is independently 5 or 6;

each b is independently 2 or 3;

|0015| Also described are pharmaceutical formulations comprising at least one compound of the invention.

{001.6) Also described herein are methods of simultaneously regulating neuropathic pain associated biochemical pathways in a patient in need thereof, by administering to the patient an effective amount of a compound of the invention.

j0017| The invention also includes pharmaceutical compositions that comprise an effective compound of the invention and a pharmaceutically acceptable carrier. The compositions are useful for treating or preventing neuropathic pais . The invention a compound of invention which provided as a pharmaceutically acceptable prodrug, a hydrate, a salt, such as a pharmaceutically acceptable salt, enantiomer_f stereoisomer,, or mixtures thereof. [0018] The present invention provides GABA derivatives accordiag to Formula I, Formula II, Formula ΙΪΪ and Formula IV as set forth below.

|0019| Described herein are compounds of Formula 1:

Formula Ϊ

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof;

Wherein

R^f is independently selected from the group consisting of hydrogen, methyl, amine, carboxyh hydroxy I, (S)-butatie-l,2-diol, 2-liydroxy aeetamide, cycohexyi methyl ether, butoxy, propoxy, thiol, alkyl, alky! thiol, acetyl thiol, disulfide, acyl,

R^* each independently represents

each a is independently 5 or 6;

each b is independently 2 or 3;

|00201 I'¹ otJher illustrative embodiments, compounds of the formula I are as set forth !xiow :

{1-1 }

( 1-2)

|0021 J Described herein ace compounds of Formula Π:

Formula 1.1

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, and stereos seiners thereof;

Wherein

R.^! is independently selected from the group consisting of hydrogen, methyl, amine, carhoxyl, hydroxy!, (S)-butane-I ,2-dioi, 2-hydroxy acetamide, cycohexyi methyl ether, butoxy, propoxy, thiol, alkyl, aikyi thiol, acetyl thiol, disulfide, acyi,

each a is independently 5 or 6;

each b is independently 2 or 3;

j0022| hi oilier illustrative embodiments, compounds of the formula U are as set forth below;

(2-2) 0023] In another aspect, compounds of formula 111 are described:

Formula III

and pharmaceutically acceptable salts, hydrates, solvates, prodmgs, enantiomers, and stereoisomers thereof;

R¹ is independently selected from the group consisting of hydrogen, methyl, amine, carboxyl, hydroxyl, (S)-butane-1 ,2-dio!, 2-hydroxy acetamide, cvcohexyl methyl ether, butoxy, propoxy, thiol, alkyl, alky! thiol, acetyl thiol, disulfide, acyl.

2 each independently represents

each a is independently 5 or 6;

each b is independently 2 or 3;

|0024| In oilier illustrative embodiments, compounds of the formula Hi are as set forth below:

(3-2)

J0025J In another aspect, compounds of formula IV are described:

Formula IV

and pharmaceutically acceptable salts, hydrates, soivates, prodrugs, ertantiomers, and stereoi som ers th ereof ;

R' is independently selected from the group consisting of hydrogen, methyl, amine, carboxyl, hydroxyl, (S)-butane-l,2-dioi, 2-hydroxy acetamide, cycohexyl methyl ether, butox , propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl,

R² each independently represents

each a is i ndependently 5 or 6;

each b is independently 2 or 3;

j0026 | below:

(4-2)

{002? J Herein the application also provides a kit comprising any of the pharmaceutical compositions disclosed herein. The kit may comprise instructions for use in the treatment of neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain or its related complications.

|0028J The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositiotis herein. In some aspects, the pharmaceutical composition is formulated for systemic administration, oral administration, sustained release, parenteral administration, injection, subdermal administration, or transdermal administration.

{0029] Herein, the application additionally provides kits comprising the pharmaceutical compositions described herein. The kits may further comprise instructions for use in the treatment neuropathic pain, diabetic neuropathic pain and other diseases related sub- chronic and chronic pain or its related complications. [0030] The compositions described herein have several uses. The present application provides, for example, methods of treating a patient suffering from neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain or its related complications manifested from metabolic conditions, genetic abnormalities, congenital disorders, chronic diseases or disorders.

DETAILED DESCRIPTION OF THE INVENTION

10031] Definitions

[0032] As used herein, the following terms and phrases shall have the meanings set forth below. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

[0033] The term "alky!" refers to the radical of saturated aliphatic groups, including straight-chain alky! groups, braached-chain aikyl groups, cycloalkyl (ali cyclic) groups, aikyl -substituted cycloalkyl groups, and cycloalkyl-substituted aikyl groups, in preferred embodiments, a straight chain or branched chain aikyl has 30 or fewer carbon atoms in its backbone (e.g., C1 -C30 for straight chains, C3-C30 for branched chains), and more preferably 20 or fewer. Likewise, preferred cyeloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure,

[0034] The term "aikyl" as used herein refers to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms. Examples of aikyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 - propyl (n-Pr, n- propyl, -CH2CH2CH3), 2-propyl (t-Pr, i-propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl - C H2CH2CH2CH3), 2-raethyl-l -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, - CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, - C(CH3)3), 1-pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (- CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2- methyl -2 -butyl (- C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3 -methyl- i -butyl (- CB2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3_.)CH2CH3), i-hexyl (~ CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2 CH3), 3-1iexyl (- CH(C,H2CH3)(C,H2Ci::12a-LV)), 2-meihyl-2~pentyl (-C(CH3)2CH2CH2CH3X 3-methyl-

2-pentyl (- CH(CH3)CH(CH3)CH2CH3), 4-methyl -2-pentyl (- CH(CH3)CH2CH(CH3)2), 3 -methyl -3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CB(CH3)2), 2 dimethyl-2-butyI (- C(CH3)2CH(CB3)2), 3,3-dimethyl- 2-butyl (-CH(CH3)C(CH3)3, !-heptyl, 1-octyl, and the like.

{^'00351 The term "alkenyi" refers to linear or branched-chain monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of imsaturation, i.e., a carbon- carbon, sp double bond, wherein the alkenyl radical includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylenyl or vinyl (-CH-CH2), ally! (-CH2CH-CH2), and the like. The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one site of unsaturation, i .e., a carbon- carbon, sp triple bond. Examples include, but are not limited to, ethynyl (-OCH), propynyl (propargyl , - CB2C-CH), and the like.

{0036] Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "un substitu ed alkyl s" and "substituted alkyis", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydrox i, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbon l (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, a amino, an amido, an amidine, an inline, a cyano, a nitro, an azido, a suifhydryl, an alkylthio, a sulfate, sulfonate, a sulfamoyl, a sulfonamido. a sultonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl ma include substituted and unsubstituted forms of amino, azido, imino, amido, phosphor)_'! (including phosphonate and phosphinate), sultonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbo.ny.ls (including ketones, aldehydes, carboxyl ates, and esters), -CF3, -CN and the like. Exemplary substituted alky Is are described below.

I S Cycloalkyls can be further substituted with alkyls, alkenyis, alkoxys, aikylthios, aminoalkyls, carbony I -substituted alkyls, -CF3, -CN, and the tike.

0037] The term "aeyl" is art-recognized and refers to a group represented by the general formula hydrocarbyl C(0)~, preferably alkylC(O)-.

[0038] "Aryl" means a monocyclic or poiycyciic ring assembly wherein each ring is aromatic or when fused with one or more rings forms an aromatic ring assembly. If one or more ring atoms is not carbon (e.g., N, S), the aryl Is a heteroaryi. Cx aryl and Cx-Y aryl are typically used where X and Y indicate the number of carbon atoms i n the ri ng.

[0039] The term "alkoxyalky!" refers to an a!kyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl

[0040] Moreover, such substituents include ail those contemplated for alkyi groups, as discussed below, except where stability is prohibitive. For example, substitution of alken l groups by one or more alkyi, carbocyclyl, aryl, heterocyclyl, or heteroaryi groups is contemplated.

{0041 j The term "alkynyl", as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted aikyny!s" arid ^"substituted alkynyl s", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alky! groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyi, carbocyclyl, aryl, heterocyclyl, or heteroaryi groups is contemplated,

[0042] The term "ether", as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or u symmetrical. Examples of ethers include, but are not limited to, heterocycle-O-heierocycle and aryl-O- heterocycle. Ethers include "alkoxyalky!" groups, which may be represented by the general formula alkyl-O-alky! . [0043] The terms "heteroaryl" and "hetaryP include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heteroaryl" and "hetaryP also include polycyclic ring systems having two or more cyclic rings in which, two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroarornatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalk.yny.ls, ary!s, heteroaryls, and/or heterocycl ls. Heteroaryl groups include, for example, pyrrole, furan, tbiophene, imidazole, oxazole, thiazole, pyrazole, pyridine., pyrazine, pyridazine, and pyrrolidine, and the like.

[0044) The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0045| The terms "heterocyclyP, "heterocycie", and "heterocyclic ' refer to substituted or unsubstituted non-aromatic ring structures., preferably 3~ to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms "heterocyclyP and "heterocyclic" also include poiycyciic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic., e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloaikynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morphoime, lactones, lactams, and the like.

[0046] The term "hydrox aikyP, as used herein, refers to an alkyl group substituted with a hydroxy group.

[0047] The term ^'"'lower^'' when used in conjunction with a chemical moiety, such as, acyl, acyioxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A 'lower aikyP, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. Lower alkySs include methyl and eth l. In certain embodiments, acyl, acyioxy, alkyl, alkenyl, alkynyl, or alkoxy subsiituents defined herein are respectively lower aeyl, lower aeySoxy, lower alk i, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear aione or in combination with other substituents, such as in the recitations hydroxyalky! and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent). 10048] The term "substituted" refers to moieties having substituents replacing hydrogen on one or more carbons of the backbone, it will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement., cycHzaiion, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds, in a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocvciic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this application, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxy!, a carbon l (such as a carboxyl, an alkox carbonyl, a formyl, or an acyl), a thiocarbonyi (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, phosphor l, a phosphate, a phosphonate, a phosphmate, an amino, an ami do, an amidine, art imine, a cyano, a nitro, an azido, a sulfhydry!, an alkylthio, a sulfate, a sulfonate, a suifamoyi, a sulfonamide, a sulfonyl, a heterocyclyf an aralkyl, or an aromatic or heteroaroroatic moiety. It will be understood by those skilled in the art thai the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

|004 ] Unless specifically stated as "unsubsiituted." references to chemical moieties herein are understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. [0050] "Substituted or unsubstituted" means thai a given moiety may consist of only hydrogen substituents through available valencies (unsubstituted) or may further comprise one or more non-hydrogen substituents through available valencies (substituted) that are not otherwise specified by the name of the given moiety. For example, isopropyl is an example of an ethylene moiety that is substituted by -CH3, In general, non- hydrogen substituent may be any substituent that ma be bound to an atom of the given moiety that is specified to be substituted. Examples of substituents include, but are not limited to, aldehyde, alicyclic. aliphatic, (Ci-io) alkyl, a!kylene, alkylidene, amide, amino, aminoalkyl, aromatic, aryl, bicydoalky!, bicyc!oaryl, carbamoyl, carboeyclyl, carboxyl, carbonyi group, cycioaU l, cycloalkylene. ester, ha o, heterobieycloalky I , heterocycloa!ky ene, heteroaryl, heterobicycloaryl, heterocycloalkyl, oxo, hydroxy, iminoketane, ketone, nit.ro, oxaalkyl and oxoalkyl moieties, each of which may optionally also be substituted or unsubstituted. In one particular embodiment, examples of substituents include, but are not limited to, hydrogen, halo, niiro, cya.no, thio, oxy, hydroxy, carbonyloxy, (Cijo) alkoxy, (C4-I 2) arySoxy, hetero (Ci- io)arySoxy, carbonyi, oxy carbonyi, aminocarbonyl.

|005l I The compounds of the present invention can be present in the form of pharmaceutically acceptable salts. The compounds of the present invention can also be present in the form of pharmaceutical ly acceptable esters (i.e., the methyl and ethyl esters of the acids of formula I, formula If formula 111 or formula IV to be used as prodrugs). The compounds of the present invention can also be solvated, i.e. liytirateci. The solvation can be affected in the course of the manufacturing process or can take place i .e. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I, formula 11, formula ΠΪ or formula IV (hydration).

|0052] Omega 3 fatty acids comprises of long chain fatty acids; eicosapentaenoic acid (CAS No. 1.0417-94-4), docosahexaenoic acid (CAS No. 6217-54-5).

[0053] GABA analogs comprises of compounds that mimic the chemical structure of the neurotransmitter gamma-ami.nobuty.ric acid (GABA). Related therapeutic drugs include, Gabapentin (CAS No. 60142-96-3), Pregabalin (CAS No. 148553-50-8), Phenibut (CAS No. 1078-21 -3), Picamilon (CAS No. 34562-97-5). 0054] Compounds thai have the same molecular formula but differ in the nature or sequence of bonding of thei r atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Diastereomers are stereoisomers with opposite configuration at one or more ehiral centers which are not eiiantiomers. Stereoisomers bearing one or more asymmetric centers that are non- superimposable mirror images of each other are termed "enaiUiomers." When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer ca t be characterized by the absolute configuration of its asymmetric center or centers and is described by the R- and S-sequencing roles of Cahn, lngold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A ehiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture" ,

{00551 As used herein, the term "metabolic condition" refers to an Inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is affected and is either deficient or completely absent. Metabolic condition associated diseases include: Hepatic, Neurologic, Psychiatric, Hematologic, Renal, Cardiovascular, Cancer, Musculoskeletal, Orthopedic and Gastroi testinal,

[0O56J The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

j^'0057| "Residue" is an art-recognized term that refers to a portion of a molecule. For instance, a residue of thioctic acid may be: dihydroJipoic acid, bisnorlipoic acid, tetranorlipoic acid, 6,8-bismeihylmercapto-octanoic acid, 4,6-bi smethy I mercapto- hexanoic acid, 2,4-bismethylmeracapto-butanoic acid, 4,6-bismethyimercapto-hexanoic acid.

[0058] The phrases "parenteral administration" and "administered parenteral ly" as used herein refer to modes of administration other than enteral and topical administration, such as injections., and include without limitation intravenous, intramuscular, intrapleural. intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra- aiticii!ar, subcapsular, subarachnoid, intraspinal and intra sternal injection and infusion. {Ό05 ) A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.

10060 j The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use i contact with the tissues of mammals, human beinas and animals without excessive toxicity, irritation, a!iergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

|0061] The phrase "pharmaceutically acceptable carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxym ethyl celluiose, ethyl celluiose and celliilose acetate; (4) powdered tragacanth; (5) mait; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, oli ve oil, com oil and soybean, oil; (10) glycols, such as propylene glycol; (1 1.) polyols, such as glycerin, sorbitol, nianniiol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; ( 15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer^' s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formul tions. [0062] The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given com pound.

[0063] The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected moieties that are hydrolyzed tinder physiological conditions to reveal the desired molecule, in other embodiments, the prodrug is converted by an enzymatic activity of the host animal.

[0064] The term "prophylactic or therapeutic" treatment is art-recognized and includes administration to the host of one or more of the subject compositions, if it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i .e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment, is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof),

1 0651 The term "predicting" as used herein refers to assessing the probability according to which a metabolic condition or neurodegenerative related diseases patient will suffer from abnormalities or complication and/or terminal renal failure and/or death (i.e. mortality) withi a defined time window (predictive window) in the future. The mortality may be caused by the central nervous system or complication. The predictive window is an interval in which the subject will develop one or more of the said complications according to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention. Preferably, however, the predictive, window is an interval of one month, six months or one, two, three, four, five or ten years after appearance of the cardiovascular complication (more preferably and precisely, after the sample to be analyzed by the method of the present invention has been obtained). As will be understood by those skilled in the art, such, an assessment is usually not in tended to be correct for 100% of the subjects to be analyzed. The term, however, requires that the assessment will be valid for a statistically significant portion of the subjects to be analyzed. Whether a portion is statisticall significant can be determined without further ado by the person skilled in the ait using various well known, statistic evaluation tools, e.g., determination of confidence intervals, p-value determination. Student's t-test, Mann- Whitney test, etc. Details are found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1 83. Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %. The p-vaiues are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001. Preferably, the probability envisaged by the present invention allows that the prediction will be correct for at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort.

0066] The term "treating" is art. -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder o condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the metabolic condition or neurodegenerative disease condition of a subject by administration of an agent even though such agent does not treat the cause of the condition. The term "treating", "treat" or "treatment" as used herein includes curative, preventative (e.g., prophylactic), adjunct and palliative treatment,

[0067] Metabolic condition related diseases or disorders includes such as neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain, and other diseases related sub-chronic and chronic pain, i-cell, Krabbe, lactic acidosis, long chain 3 hydroxyacyl CoA dehydrogenase deficiency (LCHAD), lysosomal storage diseases, mannosidosis, maple syrup urine, aroieaux-La y, metachromatic leukodystrophy, mitochondrial, Morquio, mucopolysaccharidosis, neuro-metabolic, Memann-Pick, organic acidemias, purine, phenylketonuria (.PKU), Pompe, porphyria, pseudo-Hurl er, pyruvate dehydrogenase deficiency, Sandhoff, San.fi.Uppo, Scheie, Sly, Tay-Sachs, trimethylaminuria (Fi&h-Maiodor syndrome), ure cycle conditions, NASH, or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Neurodegenerative related diseases or disorders includes such as Alzheimer's disease. Amyotrophic lateral sclerosis, Friedreich's ataxia, Huntington's disease, Lewy body disease, Parkinson's disease, Spinal muscular atrophy or any other medical condition, is well, understood in. the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.

[0068) The phrase "therapeutically effective amount" is an art -recognized term. In certain embodiments, the term refers to an amount of a salt or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment, in certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.

{^'0069 J In certain embodiments, the pharmaceutical compositions described herein are formulated in a manner such that, said compositions will be delivered to a patient in a therapeutically effective amount as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that tor 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. Typically, dosing wi ll be determined using techniques known to one skilled in the art.

0070] Additionally, the optimal concentration and/or quantities or amounts of any particular salt or composition may be adjusted to accommodate variations in the treatment parameters Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult, or child, and the nature of the disease or condition.

[0071] in certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

[0072| The term "solvate" as used herein, refers to a compound formed by solvation (e.g., a compound formed by the combination of solvent molecules with molecules or ions of tli e solute).

0073] When used with respect to a pharmaceutical composition or other material, the term "sustained release"' is art-recognized, For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically accepiable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active salt and/or composition, for a sustained or extended period (as compared to the release from a bolus). This release ma result in prolonged delivery of therapeutically effective amounts of any of the therapeutic agents disclosed herein.

[0074] The phrases "systemic admin stration," "administered systemically," "peripheral administration" and "administered peripherally" are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed systemicaiiy, may be termed "local" or "topical" or "regional" administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes,

[0075] The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a sail or composition disclosed herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may var depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirical ly determine the effective amount of a particular composition without necessitating undue experimentation.

0076] The present disclosure also contemplates prodrugs of the compositi ns di closed herein, as well as pharmaceutically acceptable salts of said prodrugs.

0077] This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the composition of a compound of Formula I, formula If formula 111 or formula IV may be formulated for systemic or topical or oral or solid or nasal or emulsions or syrups or injectables or semi-solid administration. The pharmaceutical composition may be also formulated for oral administrati n, oral solution, injection, subdermal administration, or transdermal administration. The pharmaceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

[0078] in many embodiments, the pharmaceutical compositions described herein will incorporate the disclosed compounds and compositions (Formula 1. formula IF, formula 111 or formula V) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula F, formula I I . fonnuia 111 or formula IV or composition as part of a prophylactic or therapeutic treatment. The desired concentration of formula Ϊ, formula 0, formula ΙΠ or formula IV or its pharmaceutical acceptable salts will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the salts and compositions from the subject compositions. It is to be noted that 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 he adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

[0079] ..Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula i, formula Π, formula HI or formula IV may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put. e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

[0080] The concentration and/or amount of any compound of formula I, formula II, formula 311 or formula I V may be reads iy identified by routine screening In animals, e.g., rats, by screening a range of concentration and/or amounts of the material in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the salts or compositions, and local blood flow before and after administration of therapeutic formulations disclosed herein. One such method is microanalysis, as reviewed by T. E. Robinson et al, 199 i , microanalysis in the neurosciences, Techniques, volume 7, Chapter i . The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with formula I, formula II, formula III or formula IV such as those disclosed herein are injected adjacen to the loop, released drags are collected in the dialysatc in proportion to their local tissue concentrations. The progress of diffusion of the salts or compositions may be determined thereby with suitable calibration procedures using known concentrations of salts or compositions. |O081J In certain embodiments, the dosage of the subject compounds of formula I, formula II, formula III or formula IV" provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to i finity may be used.

10082) Generally, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formula 1, formula i f formula III or formula IV is in the range of about 0.01. mg/kg/day to about 100 mg/kg day in single or divided doses, for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Formula L formula II, formula III or formula IV may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg kg day, 5 mg kg/day, 10 mg/kg/day, 20 mg kg day, 30 mg kg day, or 40 mg/kg/day. Compounds of Formula I, formula If formula Of or formula IV may also be administered to a human patient at a dose of. for example, between 0.1 mg and 1000 nig, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula 1, formula II, formula III or formula IV required for the same therapeutic benefit.

10083) An effective amount of the compounds of formul L formula II, formula 111 or formula IV described herein refers to the amount of one of said salts or compositions which is capable of inhibiting or preventing a disease. For example human neurological disease and conditions such as neuropathic pain, diabetic neuropathic pain and other diseases related sub-chronic and chronic pain

JO084] . An effective amount, may be sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a complication resulting from nerve damage or demyelizaiion and/or elevated reactive oxidative- mtrosative species and/or abnormalities in neurotransmitter homeostasis' , in patients who are at risk for such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate. The amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and oo the judgment of the prescribing physician. Thus, because of patient-to-patient variability, the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.

[0085] The compositions provided by this application may be administered to a subjec in need of treatment b a. variety of conventional routes of administration, including orally, topically, parenteral!)', e.g., intravenously, su cutaneously or intramedullary. Further, the compositions may be administered intranasally, as a rectal suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. Furthermore, the compositions may be administered to a subject in need of treatment by controlled release dosage forms, site specific drug delivery, transdermal drug delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticies.

0086] The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, exctpients and the like. Thus, for purposes of oral administration, tablets containing various exeipients such as L-argtnine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrates such as starch, alginic acid and certain complex silicates, together with binding agents such as polyvinyipyrroiidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium !auryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a simil ar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or mi lk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, eihanol, propylene glycol, glycerin and combinations thereof. The compounds of formula Ϊ, formula II, formula HI or formula IV may also comprise enterieally coated comprising of various exeipients, as is well known in the pharmaceutical art.

|0087| For parenteral admini trati n, solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

{O SSj The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 1 50 to 500 mg. or 50 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of formula 1, formula II, formula III or formula IV disclosed herein, for instance, compounds of formula I, formula 11, formula 111 or formula IV or pharmaceutical acceptable salts of a compounds of Formula I, formula II, formula II or formula IV . 0089] Generally, a composition as described herein may be administered orally, or parenteral^ (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorder that prevent, oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician. Localized admini tration may also be indicated, for example, when a high dose is desired at the target tissue or organ. For buccal administration the active composition may take the form of tablets ot lozenges formulated in a conventional mariner.

0090] The dosage administered will be dependent upon the identity of the neoplastic disease; the type of host involved, including its age, health and weight; the kind of concurrent treatment, if any; the frequency of treatment and therapeutic ratio.

[0091 J Illustratively, dosage levels of the administered active ingredients are: intravenous, 0.1 to about 200 mg/kg; intramuscular., 1 to about 500 mg kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg kg; and aerosol, 5 to about 1000 .mg kg of host body weight.

[0092] Expressed in terms of concentration, an active ingredient can be present in the com positions of the present invention for localized use about the cutis, iotranasally, pharyngolaryngeally, hro.nchi.ally, intravagtnally. rectal!y, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about I to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v,

[0093] The compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable quantities of an. active ingredient. For oral administration either solid or fluid unit dosage forms can be prepared.

[0094] Powders are prepared quite simply by comminuting the active ingredient to a suitably fine size and mixing with a similarly comminuted diluent. The diluent can be an edible carbohydrate material such as lactose or starch. Advantageously, a sweetening agent or sugar is present as well as flavoring oil.

[0095] Capsules are produced b preparing a powder mixture as hereinbefore described and filling into formed gelatin sheaths. Advantageously, as an adjuvant to the filling operation, a lubricant suc as talc, magnesium stearate, calcium stearate and the li ke is added to the powder mixture before the filling operation.

0096] Soft gelatin, capsules are prepared by machine encapsulation of slurry of active ingredients with an acceptable vegetable oil, light liquid petrolatum or other inert oil or triglyceride.

{^■0O97J Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and pressing into tablets. The powder mixture is prepared by mixing an active ingredient, suitably comminuted, with a diluent or base such as starch, lactose, kaolin, dicaleiuni phosphate and the like. The powder mixture can be granulated by wettin with a binder such as com syrup, gelatin solution, metbylcel!ulose solution or acacia mucilage and forcing through a screen. As an alternative to granulating, the powder mixture can be slugged, i.e., ran through the tablet machine and the resulting imperfectly formed tablets broken into pieces (slugs). The slugs can be lubricated to prevent sticking to the tablet- forming dies bv means of die addition of stearic acid, a stearic salt, talc or mineral oil. The lubricated mixture is then compressed into tablets.

0098] Advantageously, the tablet can be provided with a protective coating consisting of a sealing coat or enteric coat of shellac, a coating of sugar and methyl cellulose and polish coating of carnauba wax.

j0099| Fluid unit dosage forms for oral administration such as in syrups, elixirs and suspensions can be prepared wherein each teaspoon ftit of composition contains a predetermined amount of an active ingredient for administration. The water-soluble forms can be dissolved in an aqueous vehicle together with sugar, flavoring agents and preservatives to form a syrup. An elixir is prepared fay using a hydroalcoholic vehicle with suitable sweeteners together with a flavoring agent. Suspensions can be prepared of the insoluble forms with a suitable vehicle with the aid of a suspending agent such as acacia, tragacamh, rnethyleellulose and the like.

[00.I.00J For parenteral administration, fluid unit dosage forms are prepared utilizing an active ingredient and a sterile vehicle, water being preferred. The active ingredient, depending on the form and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the water- soluble active ingredient can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. Parenteral suspensions are prepared in substantially the same manner except that an active, ingredient is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The active ingredient can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to fac litate uniform distribution of the active ingredient.

[001.01.1 I addition to oral and parenteral administration, the rectal and vagina! routes can be utilized. An active ingredient can be administered by means of a suppository. A vehicle which has a melting point at about body temperature or one that is readily soluble can be utilized. For example, cocoa butter and various polyethylene glycols (Carbowaxes) can serve as the vehicle.

{ 0 1021 For intranasal instillation, a fluid unit dosage form is prepared utilizing an active ingredient and a suitable pharmaceutical vehicle, preferably P.F. water, a dry powder can be formulated when insufflation is the administration of choice.

[001031 For use as aerosols, the active ingredients can be packaged in a pressurized aerosol container together with a gaseous or liquified propellant, for example, dkhlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like, w th the usual adjuvants such as cosol ents and wetting agents, as may be necessary or desirable.

[001041 The term "unit dosage form" as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitation inherent in the art of compounding such an active material for therapeutic, use in humans, as disclosed in this specification, these being features of the present invention. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, troches, suppositories, powder packets, wafers, cachets, teaspoonfuls, tablespoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing, and other forms as herein described.

{^'00105} The tablets of the present invention contain one or more pharmaceutically active agents that are released therefrom upon contact of the tablet with a liquid medium, for example a dissolution medium such as gastrointestinal fluids, "Water soluble," as used herein in connection with non-polyrneric materials, shall mean from sparingly soluble to very soluble, i.e., not more than 100 parts water required to dissolve 1 part of the non-polymeric, water soluble solute. See Remington, The Science and Practice of Pharmacy, pp 208-209 (2000). "Water soluble," as used herein in connection with polymeric materials, shall mean thai the polymer swells in water and can be dispersed at the molecular level or dissolved in water.

{00106} As used herein, the term "modified release" shall apply to tablets, matrices, particles, coatings, portions thereof or compositions thai alter the release of an pharmaceutically active agent in an manner. Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like. Suitable mechanisms for achieving these types of modified release include diffusion, erosion, surface area control via geometry and/or impermeable barriers, or other mechanisms known in the art.

001071 In one embodiment of the invention, the first pharmaceutically active agent and the hydrophiiic polymer are mixed with a powder containing a pharmaceutically-acceptable carrier, which is also defined herein as the tablet matrix. In one embodiment, the powder has an average particle size of about 50 microns to about. 500 microns, such as between 50 microns and 300 microns. Particles in this size range are part cularly useful for direct compression processes. In embodiment, the components of powder are blended together, for example as dry powders, and fed into the die cavity of an apparatus that applies pressure to form a tablet core. Any suitable compacting apparatus may be used, including, but not limited to, conventional unitary or rotary tablet press. In one embodiment, the tablet core may be formed by compaction using a rotary tablet press (e.g., such as those commercially available from Fette America Inc., Rockaway, NX, or Manesty Machines LTD, Liverpool, UK). In general, a. metered volume of powder is filled into a die cavity (where the powder is either gravity fed or mechanically fed from a feeder) of the rotary tablet press, and the cavity rotates as part of a "die table" from the filling position to a compaction position. At the compaction position, the powder is compacted between an upper and a lower punch, then the resulting tablet cor is pushed from the die cavity by the lower punch and then guided to an injection chute by a stationary "take-off bar,

[001.081 In one embodiment of the invention., the tablet core may be a directly compressed tablet core made from a powder that is substantially free of water-soluble polymeric binders and hydrated polymers. As used herein, what is meant by "substantially free" is less than 5 percent, such as less than 1 percent, such as less than 0.1 percent, such as completely free (e.g., 0 percent). This composition is advantageous f r minimizing processing and material costs and providing for optimal physical and chemical stability of the tablet core. In one embodiment, the density of the tablet core is greater than about 0.9 g/cc.

00109| The tablet core may have one of a variety of different shapes. For example, the tablet core may be shaped as a polyhedron, such as a cube, pyramid, prism, or the like; or may have the geometry of a space figure with some non-flat faces, such as a cone, truncated cone, cylinder, sphere, torus, or the like. In certain embodiments, a tablet core has one or more major faces. For example, the tablet core surface typically has opposing upper and lower faces formed by contact with the upper and lower punch faces in the compression machine. In such embodiments the tablet core surface typically further includes a "belly-band" located between the upper and lower faces, and formed by contact with the die walls in the compression machine.

[001.101 As discussed above, the tablet core contains one or more hydrophilic polymers. Suitable hydrophilic polymers include, but are not limited to, water sweilable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and

3S mixtures thereof. Examples of suitable water swetSable cellulose derivatives include, but are not limited to, sodium carboxymethylceHulose, cross-linked hydroxypropylcelluiose, hydroxypropyl cellulose (HPC), hydroxypropylniethylcelluiose (HPMC), hydroxyisopropylceliulose, hy droxybuty lceliul ose, hydroxyphenylcellulose, hydroxyethyl cellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures thereof. Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethy!ene oxide). .Examples of suitable acrylic polymers include, but are not limited to., potassium methacrylatedtvinyibenzene copolymer, polymethylmethacrylate, high-molecular weight crosslinked acrylic acid hornopolymers and copolymers such as those commercially available from Noveon Chemicals under the tradename CARBOPOL^tM. Examples of suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin, xanthan gum, ge!lan gum, maltodextrin, galactornann.au, pusstuian, laminariii, scleroglucan, gum arabic, iriulin, pectin, gelatin, whelan, rharasan, zooglan, methylan, ch n, cyciodextrin, chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, kaolin, and lapomte; magnesium trisilicate, magnesium aluminum silicate; and mixtures thereof. Examples of suitable gelling starches include, but are not limited to, acid hydro! y zed starches, swelling starches such as sodium starch glycolate and derivatives thereof and mixtures thereof. Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrol idone, cross-linked agar, and cross-linked carboxymethylceHulose sodium, and mixtures thereof.

{001 1 J J In one embodiment, a osmogen is incorporated into the tablet core i order to draw water into the tablet upon contact with fluids, such as gastrointestinal fluids. An osmogen as used herei is a water soluble component which preferentially draws water into the tablet core for the purposes of distributing the water throughout the core, so that the active ingredient contained in the core may be released in one embodiment the osmogen is a sal t such as but not limited to sodium chloride, potassium chloride, sodium citrate, or potassium citrate.

00112) The carrier may contain one or more suitable excipients for the formulation of tablets. Examples of suitable excipients include, but are not limited to, fillers, adsorbents, binders, disintegrants, lubricants, glidants, release-modifying excipients, superdi sintegrartts, antioxidants, and mixtures thereof.

[001.131 Suitable fillers include, but are not limited to, watersoluble compressible carbohydrates such as sugars (e.g., dextrose, sucrose, maltose, and lactose), starches (e.g., corn starch), sugar-alcohols (e.g., marmitoi, sorbitol , ma!titoi, erythritol, and xy!itol), starch hydrolysates (e.g., dextrins, and ma!todextrins), and water insoluble plastically deforming materials (e.g., microcrystalHne cellulose or other cellulosic derivatives), and .mixtures thereof. Suitable adsorbents (e.g., to adsorb the liquid drug composition) include, but are not limited to, water-insoluble adsorbents such as di calcium phosphate, tricalcium phosphate, silicified microcrystalHne cellulose (e.g., such as distributed under the PROSOLV brand (PenWest Pharmaceuticals, Patterson, N Y.)), magnesium aluminometasiHcate (e.g., such as distributed under the EUSILINTM brand (Fuji Chemical Industries (USA) Inc., Robbinsville, N.J,), clays, silicas, hentonite, zeolites, magnesium silicates, hydrotalcite, veegum, and mixtures thereof.

00114) Suitable binders include, but are not limited to, dry binders such as polyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders such as water- soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymeihyiceliulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactom.an.nan, pusstulan, laminarin, scleroglucan, inulin, whe!an, rhamsan, zooglan, methylan, chitin, cyclodexirin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch glycol ate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethy!cellulose, starches, microcrystalHne cellulose, and mixtures thereof. 00115| Suitable lubricants include, but are not limited to, long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof. Suitable giidants include, but are not limited to, colloidal silicon dioxide. Suitable release-modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof.

{Ό0116} Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures thereof. Examples of suitable water- insoluble polymers include, but are not limited to, ethyl cellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, acrylates, methaerylaies, acrylic acid copolymers, copolymers thereof, and mixtures thereof. Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. Examples of suitable fats include, but are not limited to, hydrogen ated vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their salts, and mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl inonostearate, glyceryl tri stearate, glyceryl trilaurylate, glyceryl myristate, OlycoWax- 932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof. Examples of suitable phospholipids include phosphotidyi choline, phosphotidyi serene, phosphotidyi enositoi, phosphotidic acid, and mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, caiidelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate and cross- linked povidone (crospovidone). In one embodiment the tablet core contains up to about 5 percent by weight of such super dismtegrant,

|00i l7| Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfiie, butylhy droxytoi uene, butylated hydroxy anisoie, edetic acid, and edetate salts, and mixtures thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid, and mixtures thereof

{00118} The osmotic tablets of the present invention include an osmotic coating. An osmotic coating is one that is semipermeable thereby allows water to be drawn into the tablet core, e.g., for the purposes of releasing the active ingredient such as through a pre-made hole in the coating or through coati ng itself it is semipermeable membrane. The osmotic coating, thus, does not fully dissolve upon contact with water In one embodiment, the osmotic coating contains a water soluble component such as a water solibSe film former which aids in facilitating a further influx of water upon contact with water. In the current invention the osmotic coating is applied via spray coating. Suitable spray coating techniques inc ude spray coating via a coating pan or fluid bed process such as Wurster coating or top spray fluid bed coating as described in the text, "The Theory and Practice of Industrial Pharmacy", Lachroan, Leon et. al, 3rd ed. The osmotic coatin may be applied using a solution prepared with water, organic solvents, or mixtures thereof. Suitable organic solvents include but are not limited to acetone, i opropanol, methylene chloride, hexane, methanol, ethanoi, and mixtures thereof. In one embodiment the poiymer(s) are dissolved in the coating solution. In one embodiment, the po!ymer{s) are dispersed, as is the case when applying water insoluble polymers via a dispersion or as is the case when using ethylcellulose dispersions.

{^'00119} In one embodiment in which the osmotic coating functions as a semipermeable membrane (e.g., allowing water or solvent to pass into the core, but being impermeable to dissolved pharmaceutically active agent, thereb preventing the passage of pharmaceutically active agent therethrough) the film former is selected from water insoluble polymers, pH-dependent polymers, water soluble polymers, and combinations thereof. In one embodiment, the osmotic coating includes a water insoluble polymer and a pore forming material. Examples of suitable water-in soluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycapro!actones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid copolymers, and combinations thereof, in one embodiment, the water insoluble polymer is cellulose acetate. In one embodiment, the osmotic coating includes from about 10 to about 100 weight percent of a water insoluble film former.

00120) in one embodiment of the osmotic coating, the water insoluble polymer is combined with a water soluble film former in order to create pores in the resulting semipermeable membrane. Examples of suitable film formers include, but are not limited to: water soluble vinyl polymers such as poly inyl alcohol (PVA); water soluble polycarbohydrates such as hydroxy propyl starch, hydroxyethy! starch, pulluian, methyl eth l starch, carboxy methyl starch, pre-gelatiiiized starches, and film-forming modified starches, water swell able cellulose derivatives such as hydroxypropy! cellulose (HPC), hydroxyprapyJmethyl cellulose (HPMC), methyl cellulose ( C), hydroxyethylmeihy!cel!ulose (HEMC), hydroxybuty!methylceil ulose (HBMC), hydfoxyethyl ethyl cellulose (HEEC), and hydroxyethylhydroxypropylmethyl cellulose (MEMPMC); water soluble copolymers such as methacrylic acid and methacryiate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers: and mixtures thereof.

001211 I" one embodiment, a pH dependent polymer is incorporated into the osmotic coating. In one embodiment, the pH dependent polymer is used at a level of from about 10 to about 50 percent by weight of the osmotic coating. Suitable film-forming pH- dependent polymers include, but are not limited to, enteric cellulose derivatives, such as for example hydroxy-propyl methylcellulose phthaiate, hydroxypropy! methy!ce!iulose acetate succinate, and cellulose acetate phthaiate; natural resins such as shellac and zeirt; enteric acetate derivatives such as po!yvinylacetate phthaiate, cellulose acetate phthaiate, and acetaldehyde dimethylce!lulose acetate; and enteric acrylate derivatives such as for example pol methacrylate-based polymers such as poly(methacry!ic acid, methyl methacryiate) 1 :2 (commercially available from Rohm Phanna GmbH under the tradename EUDRAGIT STM), and poly(methacrylic acid, methyl methacryiate) 1: 1 (commercially available from Rohm Phanna GmbH under the tradename EUDRAGIT LTM); and combinations thereof. In one embodiment, the osmotic coating has an average thickness of at least 5 microns, such as from about 10 .microns to about 200 microns, e.g. from about 20 microns to about 1.50 microns, e.g. from about 30 to about .150 microns. In one embodiment, the osmotic coating is free of porosity (e.g., wherein the pore volume is in a pore diameter range of less than 0.01 g/ec). In one embodiment, the average pore diameter of the osmotic coating is less than about 0.2 microns (e.g., less than about 0, 15 microns).

{00122 J In one embodiment the osmotic coating is substantially free of ^pharmaceutically active agent In one embodiment the osmotic coating includes anpharmaceutically active agent which is different than the pharmaceutically active agent included in the immediate release coating. In one embodiment, the osmotic coating includes a plasticizer. In one embodiment the plasticizer must be of sufficient quantity to withstand the compression force of the immediate release coating Suitable plasticizers include, but are not limited to: polyethylene glycol ; propylene glycol; glycerin; sorbitol; tri ethyl citrate; tributyl citrate; dibutyi sebecate; vegetable oils such as castor oil, grape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates., and dioetyi-sodiitm sulfosuccinat.es; mono acetate of glycerol; di cetate of glycerol; triacetate of glycerol; natural gums; tri ace-tin; acetyl tri butyl citrate; diethy .oxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalaie; di ut i succinate, glycerol tnbutyrate; hydrogenated castor oil; fatty acids such as 1 auric acid; giycerides such as mono-, di-, and/or tri giycerides, which may be substituted with the same or different fatty acids groups such as, for example, stearic, palmitic, and oleic and the like, and mixtures thereof. In one embodiment, the plasticizer is triethyl citrate.

{^'00123} In one embodiment, at least about 50 percent of the cross- sectio al area of the osmotic coating used in tablets of this invention is striated, such as at least about 80% of the cross-sectional area of the osmotic coating portion is striated. As used herein, "striated" means non-homogeneous with respect to appearance and with respect to the internal structure of the coating portio when viewed under any magnification and lighting conditions, at which point striations or layers can be viewed. Compressed portions of a pharmaceutical oral dosage forms do not display striated areas, wherein spray coated portions display striations. For example a crossseciion of the osmotic coating portion is striated, and nonuniform with respect to refractive properties when observed utilizing a light microscope or a scanning electron microscope at a magnification of about 50 to about 400 times. The characteristic striations are indicative of the spray-coating process consisting of multiple repetitions of the steps consisting of: (a) application via spraying of coating solution; followed by (b) warm air drying, to a tumbling bed of tablets in a revolving coating pan such that numerous layers of coating material are built up as each application of coating material dries to form a layer. in one embodiment, the thickness of an individual striated layer is the range of about 10 microns to about 1 5 microns.

[001241 In certain embodiments, the osmotic coating is semipermeable (e.g., containing a plurality of small opening) and does not require the addition of a additional opening via laser or other means. In one such embodiment, the semi -permeable membrane of the osmotic coating also allows for the release of the active ingredient in the tablet core through the membrane in a zero-order or first-order release manner.

[001251 I*^{1 one} embodiment, the immediate release coating has an average thickness of at least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about 250 microns to about 1000 microns. In embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 g cc, as measured by the weight and volume of that specific layer,

{00126} In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the portions contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet, in one embodiment, the first portion includes the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent.

{001.27} In one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions contains a third pharmaceutically active agent. In one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core. 00128J in one embodiment, the outer coating portion is prepared as a dry blend of materia! s prior to addition to the coated tablet core, in another embodiment the outer coating portion is included of a dried granulation including the pharmaceutically active agent.

[00129[ In one embodiment, a suitable flavor or aroma agent may be added to the outer coating. Examples of suitable flavor and aroma agents include, but are not limited, to, essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, pee! or pulped whole fruit containing mixtures of alcohols, esters, aldehydes and lactones; essences including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavor of the fruit (e.g., strawberry, raspberry, and black currant); artificial and natural flavors of brews and liquors (e.g., cognac, whisky, rum, gin, sherry, port, and wine); tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; mint; ginger; cinnamon; cacoe/ cocoa; vanilla, liquorice; menthol; eucalyptus; aniseeds nuts (e.g., peanuts, coconuts, hazelnuts, chestnuts, walnuts, and co!anuts), almonds; raisins, arid powder, flour, or vegetable material parts including tobacco plant pans (e.g., the genus Nicotiana in amounts .not contributi g significantly to a level of therapeutic nicotine), and mixtures thereof.

J00130j Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form . Typical, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a gelatin capsule. Many methods for preparing coatings, covering or incorporating drugs, are known in the art.

[001311 The immediate release dosage, unit of the dosage form, i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a therapeutically effective quantity of the active agent with conventional pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, panicles or beads and delayed release drug-containing granules or beads), A preferred method for preparing immediate release tablets (e.g., as incorporated into a capsule) is by compressing a drugcon taming blend, e.g., blend of granules, prepared using a direct, blend, wet-granulation or dry-granulation process. Immediate release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant.. However, preferred tablets described herein are manufactured using compression rather than molding. A preferred method for forming immediate release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers)., binders, disintegrants, lubricants, glidants, and/or colorants. As an alternative to direct blending, a drug-containing blend may be prepared by using a wet-granulation or dry-granulation process. Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion. For example, a typical method for preparing drug- containing beads involves blending the active agent with conventional pharmaceutical excipients such as micfocrystaHine cellulose, starch, poly viny Ipyrrolidone, methyl cellulose, talc, metallic stearates, and silicone dioxide. The admixture is used to coat a bead core such as a sugar sphere (e.g., "non-pareii") having a size of approximately 20 to 60 mesh.

00132) An alternative procedure forpreparing drug beads is by blending tile daig with one or more pharmaceutically acceptable excipients, such as microcrystaHine cellulose, lactose, cellulose, polyvinyl pyrroiidone, talc, magnesium stearate, and a clisintegrant, extruding the blend, spheronizing the extrudate, drying and optionally coating the bead to form immediate release beads.

{001.33} Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington The Science and Practice of Pharmacy", 20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are wellknown and described in die art. The matrix devices are generally prepared by compressing the daig with a slowly dissolving polymer carrier into a tablet form. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but are not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, methylcelluSose, hydroxypropylceliulose, hydorxypropyl etl ylceliulose, sodium carboxymethylcelluiose, and Carbopolⁱ 934, and polyethylene oxides. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate. Alternatively, extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form In the latter case, the desired drug release profile can be achieved by combining, low permeability and high permeability coating materials in suitable proportion.

[001.341 A immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.

[001351 Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. These formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual diluents include inert powdered substances such as different kinds of starch, powdered, cellulose, especially crystalline and microcrystallme cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates. methylcelliilose, and polyvinylpyrrolidine can also be used. Polyethylene glycol, hydrophilic polymers, eth cellulose and waxes can also serve as binders. A lubricant is necessary in a tablet, formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as tale,

4S magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils. Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In the congealing method, the drug is mixed with a wa material and either spray-congealed or congealed and screened and processed.

£00136} Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The delayed release dosage units can he prepared, for example, by coating drug or a drug-containing composition with a selected coating material. The drag-containing composition may be a tablet for incorporation into a capsule, a tablet, for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating materials include bioerodibie, gradually hydrolyzable, gradually water-soluble, and/or eiizymatically degradable polymers, and may be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzynmtically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, ceilulosic polymers such as hydroxypropyl cellulose, hydoxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthaiate, methylceliulose, ethyl cellulose, cellulose acetate, cellulose acetate phthaiate, cellulose acetate trini ell hate and carboxymethylcelluiose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacr lic acid, methyl aery I ate, ethyl acrylate, methyl methacryiate and/or ethyl methacrylate, and other methacrylic resins thai are commercially available under the tradename EIJDRA.GITTM (Rohm Pharma; [0086] Westerstadt, Germany), including EUDRAGTTT L30D-55 and LI 00-55 (soluble at. pH. 5,5 and above). EUDRAGI.TTM 1, 1000 (soluble at pH 6.0 and above), EUDRAGITTM S (soluble at pH 7.0 and above, as a result of a higher degree of esterifi cation), and EUDRAGITTM HE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrol idone, vinyl acetate, vinvlacetate phthalate, vinyiacetate crotonic acid copolymer, and ethylene- vinyl acetate copolymer: enzymatic-ally degradable polymers such as azo polymers, pectin, chitosan, amylase and guar gum; zein and shellac. Combinations of different coating, materials may also be used. Multi-layer coatings using different polymers may also be applied. The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials, it is the combination of materials, method, and form of application that produce the desired release characteristics, which one can determine only from the clinical studies.

[00137J The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A piasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyi sebacate, trietiiyl citrate, tributyl citrate, tri ethyl acetyl citrate, castor oil and acerylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are no ionic emu! sifters such as sorbitan esters, poly sorb ates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 1 0 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such, as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti -foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition.

{001.38! Alternatively, a delayed release tablet may be formulated by dispersing tire drug within a matrix of a suitable material such as a hydrophilic polymer or a fatty

SO compound. Suitable hydrophilic polymers include, but are not limited to, polymers or copolymers of cellulose, cellulose ester, acrylic acid, methacrylic acid, methyl aery late, ethyl acry!ate, and vinyl or enzymatically degradable polymers or copolymers as described above. These hydrophilic polymers are particularly useful for providing a delayed release matrix. .Fatty compounds for use as a matrix material include, but are hot limited to, waxes (e,g. caraauba wax) and glycerol tristearate. Once the active ingredient is mixed with the matrix material, the mixture can be compressed into tablets.

[00139J A pulsed release dosage form is one that mimics a multiple dosing profile without repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared lo the drug presented as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form}. A pulsed release profile is characterized by time period of no release (lag time) or reduced release followed by rapid drug release.

(00140) Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. %, preferably 60 wt. % to 40 wt, ¾, of the total amount of active agent in the dosage form is released in the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 1 hours, and more preferably approximately 5 hours to 12 hours, following administration.

|00141] For dosage forms mimicking a three times daily dosing profile, approximately 25 wt. % to 40 wt. % of the total amount of active agent in the dosage form is released in the initial pulse, and approximatel 25 wt, % to 40 wt. % of the total amount of acti ve agent in the dosage form is released in each of the second and third pulses. For dosage forms that mimic a three times daily dosing profile, release of the second pulse preferably takes place approximately 3 hours to 10 hours, and more preferably approximately 4 to 9 hours, following oral administration. Release of the third pulse occurs about 2 hours to about 8 hours following the second pulse, which is typically about 5 hours to approximately 18 hours following oral administration.

00142) The dosage form can be a closed capsule housing at least two drug- containing dosage units, each dosage unit containing one or more compressed tablets, or may contain, a plurality of beads, granules or particles, providing that each dosage unit has a different drug release profile. The immediate release dosage unit releases drug substantially immediately following oral administration to provide an initial dose. The delayed release dosage unit releases drug approximately 3 hours to 14 hours following oral administration to provide a. second dose. Finally, an optional second delayed release dosage unit releases drug about 2 hours to 8 hours following the release of the second dose, which is typically 5 hours to 18 hours following oral administration.

[00.1.431 Another dosage form contains a compressed tablet or a capsule having a drug-containing immediate release dosage unit, a delayed release dosage unit and an optional second delayed release dosage unit. Irs this dosage form, the immediate release dosage unit contains a plurality of beads, granules particles that release drug substantially immediately following oral administration to provide an initial dose. The delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.

[00144] An optional second delayed release dosage unit contains coated beads or granules that release drug about 2 to 8 hours following administration of the initial delayed release dose, which is typically 5 to 18 hours following oral administration. The beads or granules in the delayed release dosage unites) are coated with a bioerodibie polymeric material. This coating prevents the drug from being released until the appropriate time, i.e., approximately 3 hours to less than 14 hours following oral administration for the delayed release dosage unit and at least 5 hours to approximately 18 hours following oral administration for the optional second delayed release dosage unit, in this dosage form the components may be admixed in the tablet or may be layered to form a l mi ated tablet. 00145| Another dosage form is a tablet having a drag-containing immediate release dosage unit, a delayed release dosage unit, and an optional second delayed release dosage unit, wherein the immediate release dosage unit comprises an outer layer that releases the drug substantially immediately following oral administration. The arrangement of the remaining delayed release dosage(s), however, depends upon whether the dosage form is designed to mimic twice daily dosing or three times daily dosing,

[001.461 In the dosage form mimicking twice daily dosing, the delayed release dosage unit contains an inner core that is coated with a bioerodible polymeric material . The coating is applied such that release of the drug occurs approximately 3 hours to less than 14 hours following oral administration. In this form, the outer layer completely surrounds the inner core, in the dosage form mimicking three times a day dosing, the (first) delayed release dose contains an internal layer that releases drug approximately 3 hours to less than 14 hours following oral administration. This internal layer is surrounded by the outer layer. The second delayed release dosage unit generally contai s an inner core that releases the drug at least 5 hours to approximately 18 hours following oral administration. Thus, the layers of this tablet (starting from the external surface) contain an outer layer, an internal layer and an inner core. The inner core contains delayed release beads or granules. Furthermore, the internal layer contains the drug coated with a bioerodible polymeric material. Alternatively, in this particular dosage form mimicking three times day dosing, both the delayed release dosage unit and second delayed release dosage units are surrounded by an inner layer. This inner layer is free of active agent. Thus, the layers of this tablet (starting from the external surface) comprise an outer layer, inner layer and an admixture of the delayed release dosage units. The first deiayed release pulse occurs once the inner layer is substantially eroded thereby releasing the admixture of the deiayed release dosage units. The dose corresponding to the (first) delayed release dosage unit is released immediately since the inner layer has prevented access to this dose for the appropriate time, e.g., from approximately 3 hours to 10 hours. The second delayed release dose, however, is formulated to effectively delay release for at least 5 hours to approximately 18 hours following oral administration, 00147) For formulations mimicking twice daily dosing, it is preferred that the delayed release dose is released approximately 3 hours to up to 14 hours, more preferably approximately 5 hours to up to 12 hours, following oral administration. For formulations mimicking three times daily dosing, it is preferred that the (first) delayed release dose is released approximately 3 to 10 hours, preferably 4 hours to 9 hours, following oral administration. For dosage forms containing a third dose, the third dose (i.e., the second delayed release dose) is released at least 5 hours to a roximatel .18 hours following oral administration.

100148| In still another embodiment, a dosage form is provided which contains a coated core-type delivery system wherein the outer layer contains an immediate release dosage unit containing an active agent, such that the active agent therein is immediately released following oral administration; an intermediate layer there under which surrounds a core; and a core which contains immediate release heads or granules and delayed release heads or granules, such that the second dose is provided by the immediate release heads or granules and the third dose is provided by the delayed release beads or granules.

[00149| For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1 % to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared.

{Ό015Θ} Methods of preparing various pharmaceutical compositions with a certain amount of one or more compounds of formula i, formula if formula HI or formul a IV or other active agents are known, or will be apparent in light of this disclosure, to those skilled i this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

[00.1.5.1. J In addition, in certain embodiments, subject compositions of the present application maybe lyophilized or subjected to another appropriate drying technique such as spray drying. The subject, compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.

00152) Formulations useful in the methods provided herein include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amoimi of a subject composition which may be combined with a earner material t produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.

[00153[ Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients, in general , the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[00154) The compounds of formula I, formula 11. formula ΠΪ or formula IV described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy. The final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or 0.01 -1.0% w/w, of medicament relative to the total weight of the formulation.

1001.55) It is desirable, but by no means required, that the formulations herein contain no components which may provoke the degradation of stratospheric ozone. In particular it is desirable that the formulations are substantially free of ch!orofluorocarbons such as CC13F, CC12F2 and CF3CC13. As used to refer to ozone- damaging agents, "substantially free" means less than 1% w/w based upon the propel!ant system, in particular less than 0.5%, for example 0. 1% or less.

[00156) The propel! ant may optionally contain an adjuvant having a higher polarity and/or a higher boiling point than the propellant. Polar adjuvants which may be usee! include (e.g., C2-6) aliphatic alcohols and polyols such as ethanol, isopropanol and propylene glycol. In general, only small quantities of polar adjuvants (e.g., 0.05-3.0% w/w) may be required to improve the stability of the dispersion— the use of quantities in excess of 5% w/w may tend to dissolve the medicament. The formulations described herein may contain less than 1% w/w, e.g., about 0, !% w/w, of polar adjuvant. However, the formulations may be substantially free of polar adjuvants, such as ethanol. Suitable volatile adjuvants include saturated hydrocarbons such as propane, -butane, isobutane, pentane and isopentane and alkyi ethers such as dimethyl ether. In general, up to 50% w/w of the propei!ant .may comprise a volatile adjuvant, for example 1 to 30% w/w of a volatile saturated C1 -C6 hydrocarbon.

|00157| Optionally, the aerosol formulati ns may further comprise one or more surfactants. The surfactants must be physiologically acceptable upon administration by inhalation. Within this category are included surfactants such as L-a-phosphatidylchoiine (PC), 1,2-dipalmHoylphosphatidychoiine (DPPC), oleic acid, sorbitan trioleate., sorbitan mono-oleate, sorbitan monolaurate, poly oxy ethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monooleate, natural lecithin, oleyl poly oxy ethylene (2) ether, stearyl poly oxy ethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxy ethylene and oxy propylene, synthetic lecithin, di ethyl ne glycol dioleate, tetrahydrofurturyl oleate, ethyl oleate, isopropyl ra ri state, glyceryl monooleate, glyceryl monostearate, glyceryl monoricinoleate, cetyi alcohol, stearyl alcohol, polyethylene glycol 400, cetyi pyridiiiium chloride, benzalkonium chloride, olive oil, glyceryl monolaurate, com oil, cotton seed oil, and sunflower seed oil. Appropriate surfactants include lecithin, oleic acid, and sorbitan trioleate.

{00158! Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the disclosures herein

[00159[ Certain pharmaceutical compositions disclosed herein suitable for parenteral administration comprise one or more subject compositions in combination with one or more pharmaceutically acceptable sterile, isotonic, aqueous, or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriosiats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

00160) Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions include water, ethanol, poiyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

{00161 } Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacaiitb), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil n- water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin., or sucrose and acacia), each containing a pfedeiermined amount of a subject composition as an active ingredient. Subject compositi ns may also be administered as a bolus, electuary,, or paste.

00162| in solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptabie earners and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymefhyicellulose, alginates, gelatin, polyvinyl pyrrol idone, sucrose and/or acacia; (3) humectants, such as glycerol: (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca, starch, afgmic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

{^'00163} A tablet may foe made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disiniegrant (for example, sodium starch giyeolate or cross-linked sodium carbox methyl cellulose), surface-altering or dispersing agent. Molded tablets may be made by molding in a suitable machine a .mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

{00164} There has been widespread use of tablets since the latter part of the 19th century and the majority of pharmaceutical dosage forms are marketed as tablets. Major reasons of tablet popularity as a dosage form are simplicity, low cost and the speed of production. Other reasons include stability of drug product, convenience in packaging, shipping and dispensing. To the patient or consumer, tablets offer convenience of administration, ease of accurate dosage, compactness, portability, blandness of taste, ease of administration and elegant distinctive appearance.

00165| Tablets may be plain, film or sugar coated, bisected, embossed, layered or sustained- release. They can be made in a variety of sizes, shapes and colors. Tablets may be swallowed, chewed or dissolved in the buccal cavity or beneath the tongue. They may be dissolved in water for local or topical application. Sterile tablets are normally used for parenteral solutions and for implantatio beneath the skin.

{00166} In addition to the active or therapeutic ingredients, tablets may contain a number of inert materials known as excipients. They may be classified according to the role they play in the final tablet. The primary composition may include one or more of a filler, binder, lubricant and glidant Other excipients which give physical characteristics to the finished tablet are coloring agents, and flavors (especially in the case of chewabie tablets). Without excipients most drugs and pharmaceutical ingredients cannot be

SS directly-compressed into tablets. This is primarily due to the poor flow and cohesive properties of most drags. Typically, excipients are added to a formulation to impart good flow and compression characteristics to the material being compressed. Such properties are imparted through pretreatmerii steps, such as wet granulation, slugging, spray drying spheromzation or crystallization.

{^■00167} Lubricants are typically added to prevent the table-ting materials from sticking to punches, minimize friction during tablet compression, and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually of about 1% by weight.

[001.68} Other desirable characteristics of excipients include the following: high- compressibility to allow strong tablets to be made at low compression forces; impart cohesive qualities to the powdered material; acceptabie rate of disintegration; good flow properties thai can improve the Sow of other excipients i the formula; and cohesiveness (to prevent tablet from crumbling during processing, shipping and handling).

{00169} There are at least three commercially important processes for making compressed tablets: wet granulation, direct compression and dry granulation (slugging or roller compaction). The method of preparation and type of excipients are selected to give the tablet formulation the desired physical characteristics that allo for the rapid compression of the tablets. After compression, the tablets must have a number of additional attributes, such as appearance, hardness, disintegrating ability and an acceptable dissolution profile. Choice of fillers and other excipients will depend on the chemical and physical properties of the daig, behavior of the mixture during processing and the properties of the final tablets. Preformulation studies are done to determine the chemical and physical compatibility of the active component with proposed excipients

[001.70} The properties of the drug, its dosage forms and the economics of the operation will determine selection of the best process for tableting. Generally, both wet granulation and direct compression are used in developing a tablet.

|00171| One formulation comprises the following: a compound of Formula L formula II, formula ΠΪ or formula IV and a binder. Examples of pharmaceutically acceptabie binders include, but are not limited to, starches; ceOuloses and derivatives thereof, e.g., microcrystalline cellulose, hydroxypropyi ceiiulose hydroxylethyl ceiiulose aod hydroxylpropylraethyl cellulose; sucrose; dextrose; corn syrup; polysacchartdes; and gelatin. The binder, e.g., may be present in an amount from about 1 % to about 40% by weight of the composition such as 1 % to 30% or I % to 25% or 1 % to 20%. 00172| Optionally, one, two, three or more diluents can be added to the formulations disclosed herein. Examples of pharmaceutically acceptable fillers and pharmaceutically acceptable diluents include, but are not limited io, confectioner's sugar, compressible sugar, dextrates. dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc. The filler and/or diluent, e.g., may be present in an amount from about 15% to about 40% by weight of the composition. In certain embodiments, diluents are microcrystalline ceiiulose which is manufactured by the controlled hydrolysis of al ha-cellulose, obtained as a pulp from fibrous plant materials, with dilute mineral acid solutions. Following hydrolysis, the hydroceliulose is purified by filtration and the aqueous slurry is spray dried to form dry, porous particles of a broad size distribution. Suitable microcrystalline ceiiulose will have an average particle size of from about 20 nm to about 200 nm, Microcrystalline cellulose is available from several suppliers. Suitable microcrystalline cellulose includes Avicei PH 101, Avicei PH 102, Avicei PH 103, Avicei PH 105 and Avicei PH 200, manufactured by FMC Corporation. The microcrystalline cellulose may be present in a tablet formulation in an amount of from about 25% to about 70% by weight. Another appropriate range of this material is from about 30% to about 35% by weight; yet another appropriate range of from about 30% to about 32% by weight. Another diluent is lactose. The lactose may be ground to have an average particle size of between about 50 pm and about 500 pm prior to formulating. The lactose may be present in the tablet formulation in an amount of from about 5% to about 40% by weight, and can be from about 18% to about 35% by weight, for example, can be from about 20% to about 25% by weight. 00173| Optionally one, two, three or more disintegrants can be added to the formulations described herein. Examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross- linked polyvinyl pyrro!idone, cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose; soy polysaccharides, and guar gum. The disintegrant, e.g., may be present in an amount from about 2% to about 20%, e.g., from about 5% to about 10%, e.g., about 7% about by weight of the composition. A disintegrant is also an optional but useful component of the tablet formulation. Disintegrants are included to ensure that the tablet, has an acceptable rate of disintegration. Typical disintegrants include starch derivatives and salts of carboxymefchy lcell u!ose. Sodium starch gl col ate is one appropriate disintegrant for this formulation. In certain embodiments, the disintegrant is present in the tablet formulation in an amount of from about 0% to about 1.0% by weight, and can be from about 1% to about 4% by weight, for instance from about 1.5% to about 2.5% by weight.

(00174J Optionally one. two, three or more lubricants can be added to the formulations disclosed herein. Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium triplicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and macrocrystalline cellulose. The lubricant, e.g., may be present in an amount from about 0.1% to about 5% by weight of the composition; whereas, the glidant, e.g., may be present in an amount from about 0. 1% to about 10% by weight. Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight. The lubricant component ma be hydrophobic or hydrophilic. Examples of such lubricants include stearic acid, talc and magnesium stearate. Magnesium stearate reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. Magnesium stearate also aids in the flow of the powder in the hopper and into the die. It has a particle size range of 450-550 microns and a density range of .1.00-1.80 g/niL It is stable and does not polymerize within the tabletiiig mix. One lubricant, magnesium stearate may also be employed in the formulation. In some aspects, the lubricant is present in the tablet formulation in an amount of from about 0.25% to about 6%; also appropriate is a level of about 0.5% to about 4% by weight; and from about 0.1% to about 2% by weight. Other possible lubricants include talc, polyethylene glycol, silica and hardened vegetable oils. In an optional embodiment, the lubricant is not present in the formulation, but is sprayed onto the dies or the punches rather than being added directly to the formulation.

00I 75| Examples of useful excipienta which can optionally be added to the composition are described in the Handbook of Pharmaceutical Excipients, 3rd edition. Edited by A.H.Kibbe, Published by: American Pharmaceutical Association. Washington DC, ISBN: 0-917330-96-X, or Handbook of Pharmaceutical Excipients (4th edition). Edited by Raymond€ Rowe ~ Publisher: Science and Practice.

|00176| Liquid dosage forms for oral administratio include pharmaceutically acceptable emulsions, mtcroemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilteiog agents and emu! si tiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyiene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

|001771 Suspensions, in addition to the subject compositions, may contain suspending agents such as, for example, ethoxyiaied isostearyi alcohols, pol ox ethylene sorbitol, and sorbitan esters, macrocrystalline cellulose, aluminum, rnetahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[00178] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax., or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and release the encapsulated compound(s) and composition(s). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropri te.

I 0179J Dosage forms for transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. A subject composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required . For transdermal admini tration, the complexes may include lipophilic and h drophilic groups to achieve the desired water solubility and transport properties.

{0 180} The ointments, pastes, creams and gels may contain, in addition to subject compositions., other carriers, such as animal and vegetable fats, oils, waxes., paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, benfconites, silicic acid, talc and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and poly amide powder, or mixtures of such substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

001811 Methods of delivering a composition or compositions via a transdermal patch are known in the art. E em lar}'' patches and methods of patch delivery are described in US Patent Mos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983,

6,239, I SO, and 6, 103,275.

00182) In one embodiment, a transdermal patch may comprise an outer backing foil, a. matrix and a protective liner wherein a) the composition or compositions are present in the matrix in a solution (which may be oversaturated), b) the matrix may contain 1 to 5% activated Si02, and c) the matrix may have a moisture content of less than 0.7%. Moisture-free matrix patches which contain activated silicon dioxide in the matrix show an enhanced drug release into the skin. 00183| In another embodiment, a transdermal patch may comprise; a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane composite and 2-10 parts by weight of a styrene-ethylene-butylene-siyrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkyiene terephthalate fil m adhered to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the polyalkyiene terephthalate film; and a second adhesive layer comprising a siyrene-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer, A method for the manufacture of the above-mentioned substrate sheet comprises preparing the above resin composition molding the resin composition into a composite film by a calendar process, and then adhering a polyalkyiene terephthalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkyiene terephthalate film.

001841 fte pharmaceutical compositions herein can be packaged to produce a

^"reservoir type" transdermal patch with or without a rate-limiting patch membrane. The size of the patch and or the rate limiting membrane can be chosen to deliver the transdermal flux rates desired. Such a transdermal patch can consist of a polypropylene/polyester imperv ious backing member heat-sealed to a polypropylene porous/permeable membrane with a reservoir there between. The patch can include a pharmaceutically acceptable adhesive (such as a acrylate, silicone or rubber adhesive) on the membrane layer to adhere the patch to the skin of the host, e.g., a mammal such as a human. A release liner such as a polyester release Hoer can also be provided to cover the adhesive layer prior to application of the patch to the ski as is conventional in the art. This patch assembly can be packaged in an aluminum foil or other suitable pouch, again as is conventional i the art.

J00185J Alternat vely, the compositions herein can be formulated into a "matrix- type" transdermal patch. Drug Delivery Systems Characteristics and Biomedical Application, R. L Julia.no, ed„, Oxford Uni ersity Press, .Y. (1980); and Controlled Drug Delivery, Vol, I Basic Concepts, Stephen D. Brack (1983) describe the theory and application of methods useful for transdermal delivery systems. The daig-matrix could be formed utilizing various polymers, e.g. silicone, polyvinyl alcohol. The "drug matrix" may then be packaged into an appropriate transdermal patch.

00186| Another type of patch comprises incorporating the drug directly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane. The drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.

[001.871 Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule daigs.

[001881 iontophoresis is a technique e ployed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances molecular transport across the skin are (a) repelling a charged ion from an electrode of the same charge, (b) e!ectroosmosis, the convective movement of solvent that occurs through a charged pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current.

[00189) In some cases, it may be desirable to administer in the form of a kit, it ma comprise a. container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous whe the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician. [00190| An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a plastic material that may be transparent. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction i which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet, in some embodiments the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

METHODS FOR MAKING THE GABA DERIVA TIVES

[001911 Examples of synthetic pathways useful for making GABA derivatives of Formula 1, Formula IT Formula III, and Formula IV are set forth in the examples below and generalized in the schemes 1 ··· 4,

Scheme-! :

{001 2 j Step -1 : Synthesis of Compound 2:

{00193} ^'TO the solution of sodium hydride ( 1.0 mmol) in ( 10 vol) of tetra hydrofuran (TRF), cyclohexane nitrite 1 (i 0 mmol) in {10 vol) of THF was added drop wise at if C and left for stirring for 0.5 h, terf-Batyl chloroacetate (10 vol) was added simultaneously at room temperature and left for stirring for 2 h. After the Reaction completion (monitored by TLC), die reaction mixture was portioned between diethyl ether (2L) and water (2 L), followed by washing organic layer with brine solution ( 1 L), the organic layer was dried over anhydrous Na^SOsand evaporated under reduced pressure to form product 3 which was recrystali ed in hexane (50 vol) to yield 6S % of compound 3 as a semi- white solid. 001941 Step -2; Synthesis of Compound 3;

1 01.95 Raney Ni (moist weight 0.64 g. approximately lOmmol) and dry iert-butanol ( J O vol) were placed in a 50 mL flask, and then corapound-2 ( 10 mmol) was added while stirring. Flushed with nitrogen and followed by hydrogen gas. Reaction was left stirring for vigorously at room temperature for 45 min hydrogen atmosphere. On completion of the reaction, the mixture was filtered. The organic layer was evaporated and residue was dissolved i« ethyl acetate, and was washed with, water. The organic layers were dried and evaporated, and the product was purified by flash column chromatography on silica gel to give compound-3 as pale yellow liquid (yield: 92%). 0()1961 Step -3: Synthesis of Compound 4:

1001971 Compound 3 (1,0 mmol) arid 2,4-dimediox benzyl amine ( 1.0 mmol) was taken in 1,2 Diehloromethane (20 vol; LR grade) and stirred for 2h at room temperature for imine formation, then sodium triacetoxy borohydride ( 1,5 mmol) was added portion wise at 0°C and the reaction mixture was allowed to stir for 4-6 h at T. On completion of the reaction (monitored by TLC). the reaction mixture was diiuted with DCM (50 vol), washed with water (50 vol) followed by brine solution (50 voi)_: dried over anhydrous Na₃SO^ and evaporated under reduced pressure to get crude product as viscous oil which was purified by column chro atography over neutral alumina by using 30 % ethyl acetate-pet ether as eluerrt to yield 80 % of compound 4 as a pale yellow liquid.

6S [00 -4; Synthesis of Compound 6;

[O0199| To a solution of compound 4 ( 1.0 mmol) in dry DCM (1.8 L) was added N, N- ditsopropylethyiamine (2.0 mmoi) at ~10°C, followed by drop wise addition of 1~ cMoroet ylehlorof miate (1 .2 mmoi) for 30 rtiin at the same temperature and the reaction mixture was allowed to stir for 1 at 0^':'C. On completion of the reaction (monitored by TLC), the reaction mixture intermediate 5 was directly used for the next step without further isolation and purification.

[002001 another RB flask die cis-5,8,1 1 J 4J 7-Bieosapeotaersoic acid (1.2 mmol) and anhydrous KJCO_J (3.0 mmol) was taken in dry DMF (10 vol) stirred at room temperature for 2 h and then cooled to -10 ^,;'C. intermediate 5 was added slowly drop wise over 30 min and then was allowed to stir at room temperature lor 12 h. Reaction was monitored by TLC. On compietion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with diethyl ether (2 x I L). The combined organic layers were washed with water (2 x 500 mL) followed by brine solution (100 mL), dried over anhydrous Na;»SO,s and evaporated under reduced pressure. The etude was purified by column chromatography over 100-200 mesh silica gel fay using 0% to 20% ethyl acetate in pet ether as an e!uent to yield 40% of compound 6 as a yellow liquid. 002011 Step -5; Synthesis of Compound 7:

{00202} 25% TFA in DCM was added to compound 6 ( 1.0 mmol) at 0 and the reaction mixture was allowed to stir for 30 rain at the same temperature. Reaction was monitored by TLC, On completion of the reaction, the reaction mixture was basified with saturated Na₂C0₃ solution (20 vol) and extracted with. DCM (20 vol), dried over anhydrous a^SC^ and evaporated under reduced pressure. The crude was purified by column chromatography over neutral alumina (Merck) by using 30 % ethyl acetate-pet ether as eluent to yield 51 ,6 % of compound 7 as a pale yellow serai-solid.

Scheme -2:

002031 Step - I : Synthesis of Compound 2:

{00204} Compound 1 (1.0 rnmoi) and

benzyl amine (1.0 mmol) taken in

Methanol (20 voi; LR grade) aid stirred for 12 h at room temperature for inline formation, men sodium borohyride (1.0 mmol) was added portion wise at 0 ° and the reaction mixture was allowed to stir for 2 h at rt. On completion of the reaction (monitored by TLC). the reaction mixture was concentrated under reduced pressure and was diluted with DCM (.50 voi), washed with water (50 voi) followed by brine solution (50 voi), dried over anhydrous NfeSO* and evaporated under reduced pressure to get erode product as viscous oil which was purified by column chromatography over neutral alumina by using 30 % ethyl acetate-pet ether as eluesnt to yield 70 % of compound 2 as a pale yellow liquid.

{00205} Step -2: Synthesis of Compound 3:

{00206} Concentrated suifuric acid (0.55 .mL, 10 mmol) was added to a vigorously stirred suspension of anhydrous magnesium sulfate (4.81 g, 40 mmol) in 40 mL of Dichloromethane. The mixture was stirred for 1 mm. after which the carboxylic acid derivative 2 (10 mmol) is added, tert ~ Buty l alcohol (50 mmol) was added at the end into the reaction, mixture. The mixture was kept air tight and stirred for 18 h at 25 ⁰ C, or until the reaction is complete and monitored by TLC analysis. The reaction mixture is then quenched with 75 mL of saturated sodium bicarbonate solution and stirred until all magnesium sulfate has dissolved. The solvent phase is separated, washed with brine, dried ( gSOj), and concentrated to afford the crude leri · butyl ester, which is purified by chromatography to provide eompound-3.

f00207| Step -3: Synthesis of Compound 6:

{00208} To a solution of compound 3 { 1 ,0 mmol) in dry DC (1.8 L) was added . N- diisopropyleraySanime (2.0 mmol) at -10°C, followed by drop wise addition of 1 - chioroethylchloroformate (i .2 mmol) for 30 min at the same temperature and the reaction mixture was allowed to stir for 1 fa at 0^CC, On completion of the reaction (monitored by TLC), the reaction mixture intermediate 4 was directly used for the next step without further isolation and purification.

f 00209} In another RB flask the cis-5,S,l K14, 17-Eicosape.nlaenoic acid 5 ( 1 .2 mmol) & anhydrous ;C0₃ (3.0 mmol) was taken in dry DMF ( It⁾ vol) stir at room temperature for 2 h and then cooled to -10 ^i!Cl intermediate 5 was added slow ly drop wise over 30 min. & then was allowed to stir at room temperature for 12 h. Reaction was motvitored fay TLC. On completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with diethyl ether (2 x .1 L). The combined organic layers were washed with water (2 x 500 mL) foliowed by brine solution (100 mL), dried over anhydrous Na₂S0 and evaporated under reduced pressure.

The crude was purified by column chromatography over 100-200 mesh silica gel by using 0 to

20% ethyl acetate in pet ether as an eiueirt to yield 48 % of compound 6 as a yellow viscous liquid. 00210| Step -4; Synthesis of Compound 7:

|0021 J 25% TFA in DCM was added to compound 6 { i .0 mrool) at 0 X and the reaction mixture was allowed to stir for 30 mm at the same temperature. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was basified with saturated NajCO?, solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous NajSO* and evaporated under reduced pressure. The crude was purified by coitimu chromatography over neutral alumina (Merck) by using 30 % ethyl acetate-pet ether as eluerst to yield 62 % of compound 7 as a pale yellow semi-white amorphous solid.

Scheme -3:

[00212] Step -1: Synthesis of Compound 3;

2 ³

} 00213] To the solution of sodium hydride {1.0 mmol) in (10 vol) of tetrahydrofiiran (THF), cyclohexane nitrite 1 (1.0 mmol) in (10 vol) of THF w s added drop wise at 0^UC and left for stirring for 0.5 h, rm-Butyl chlor acetate (10 vol) was added simultaneously at room temperature and left for stirring for 2 h. Reaction completion (monitored by TLC). the reaction mixture was portioned between diethyl ether (2L) and water (2 L), followed by washing organic layer with brine solution (1 L), the organic layer was dried over anhydrous N¾S0 and evaporated under reduced pressure to get product 2 which was recrystalized n hexane (50 vol) to yield 325 g (45,7 %) of compound 2 as a semi w hite solid.

(00214| Raney Ni (moist weight 0.64 g, approximately lOmrnol) and dry tert-butanoJ (10 vol) were placed in a 50 mL flask, and then compound-2 ( 10 mmol) was added while stirring. Flused with nitrogen & followed by hydrogen gas. Reaction left stirring for vigorously at room temperature for 45 rnin at hydrogen atmosphere, on completion the reaction mixture was filtered. The organic layer was evaporated and residue was dissolved in ethyl acetate, and was washed with water. The organic layers were dried over sodium sulfate, filtered and evaporated, and the product was purified by flash column chromatography on silica ge! to give compound -3 as pale white liquid (yield: 92%).

[00215]

3 4

[00216] Compound 3 ( 1.0 mmol) and 2,4-dimet.hoxy benzyl amine (1.0 mmol) was taken in 1,2 Dichloromethane (20 vol; LR grade) and stirred for 2h at room temperature for inline formation, then sodium triacetoxy borohydride (1.5 mmol) was added at 0 "C and the reaction mixture was allowed to stir for 4-6 h at rt. On completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (50 vol), washed with water (50 vol) followed by brine solution (50 vol), dried over anhydrous Na_¾S0₄ and evaporated under reduced pressure to get crude product as viscous oil which was purified by column chromatography over neutral alumina by using 30 % ethyl acetate-pet ether as elueat to yield 80 % of compound 4 as a semi-solid.

{00218| To a solution of compound 4 { 1 ,0 rornol) in dry DCM (1.8 L) was added . N- diisopropylethyi.««iiie {2.0 mmol) at -M)°C, followed by drop wise addition of 1 - chtoroethylchlorolbrniate (i .2 mmol) for 30 min at the same temperature and the reaction mixture was allowed to stir for 1 fa at 0^RC, On completion of the reaction (monitored by TLC), the reaction mixture intermediate 5 was directly used for the next step without further isolation and purification.

{00219} In another RB flask the cis-5,8.1 i.l4_y17-Eicosapentaenoic acid (1 .2 mmol) & anhydrous K.₂C<¼ (3.0 mtnol) was taken in diy DMF ( 1.0 vol) stir at room temperature for 2 h and then cooled to -10 "C, intetmediate 5 was added slowly drop wise over 30 min. & then was allowed to stir at room temperature for 12 h. Reaction was monitored fay TLC. On completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with diethyl ether (2 x 1 L). The combined organic layers were washed with water (2 x 500 mL) followed by brine solution (100 mL), dried over anhydrous

and evaporated under reduced pressure. The crude was purified by column chromatography over 100-200 mesh silica gel by using 0 to 20% ethyl acetate in pet ether as an eiiient to yield 40% of compound 6 as a yellow liquid.

|00220| Step -4; Synthesis of Compound 7:

25% TFA in DCM was added to compound 6 ( 1.0 mmol ) at 0 °C and the reaction mixture was allowed to stir for 30 min at the same temperature. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was basitled with saturated aaCOa solution (20 vol) and extracted with DCM (20 vol), dried over anhydrous

and evaporated under reduced pressure. The crude was purified by column chromatography over neutral alumina (Merck) by using 30 % ethyl acetate-pet ether as eluent to yield 51.6 % of compound 7 as a pale white viscous semi-soiid.

Scheme -4:

7S [002211 Step -1 : Synthesis of Compound 2:

[00222} To the solution of Benzyl 4-aminobutanoate (200.0 g, 165.2 mmol; 1.0 eq) in N.N-Dimethyl formamide, diisopropyi ethyiamine (2.0 lumoi}, nicotinoyl chloride 1 ( 1.0 mmol) was added drop wise for 0.5 h at 0 ^<;'C, The reaction mixture is brought to room temperature and left for stirring for 3 h. On completion of the reaction (monitored by TLC). the reaction mixture was diluted with ethyl acetate (50 vol) and washed with water (40 vol), followed by brine solution (20 Vol), the organic layer was dried over anhydrous _;SO^ and evaporated under reduced pressure to get: product 2 which was recrystalized in hexane (20 V) to yield (96 %) of compound 2 as of white solid.

|00 -2; Synthesis of Compound 3:

[002241 10% Palladium charcoal (lOmmol) and dry Methanol (10 vol) were placed in a

50 mL flask, and then compound- 2 (10 mmol) was added while stirring. Flushed with nitrogen and followed by hydrogen gas. Reaction left for stirring vigorously at room temperature for 2.0 h at hydrogen atmosphere, on completion the reaction mixture was filtered over celite and washed with methanol. The organic layer was evaporated and residue was dissolved in ethyl acetate, and was washed with water. The organic layers were dried over sodium sulfate, filtered and evaporated to yield compound-3 (yield: 90%). | 0225| Step -3: Synthesis of Com pound 6:

0 2261 T° ^a solution of eis-5,8; U J J 7-Eicosapentaenoic acid 4 ( 1.0 mmol} in dry

DCM (Ί..8 1.) was added N. N-diisopropylethylamine (2.0 mmol) at -10°C, foliovved by drop wise addition of 1 -chloroemyichloroformaie (1 .2 mmol) for 30 min. at the same temperature and the reaction mixture was aliowed to stir for 1 h at 0"C. On completion of the reaction (monitored by TLC), the reaction mixture intermediate 5 was directly used for the next step without further isolation and purification.

[002271 In another RB flask the Compound-3 (.1.2 mmol) and anhydrous K₃CO_? (3.0 mmol) was taken in dry- DMF (10 vol) stir at room temperature for 2 h and then cooled to -10^''C, intermediate 5 was added slowly drop wise over 30 min. & then was allowed to stir at room temperature for 12 h. Reaction was monitored by TLC. On completion of the reaction, the reaction mixture was poured into water (100 mL) and extracted with diethyl ether {2 x I L). The combined organic layers were washed with water (2 x .500 mL) followed by brine solution (100 mL), dried over anhydrous ^' a₂SO« and evaporated under reduced pressure. The erode was purifted by column chromatography over 100-200 mesh silica gel by using 0 to 20% ethyl acetate in pet ether as an elitent to yield 40% of compound 6 as a pale colorless liquid. EXAMPLES 00228) The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to il lustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be understood that resort may be had to various other embodiments, modifications and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and or scope of the appended claims. Example ~ I :

|00229| Pharmacokinetic (PK) parameters of illustrative com ounds of

Formula.™ I (1-1) of the invention in comparison with the PK parameters of the anti-epileptic drug, gabapentin hydrochloride.

[00230J The clinical pharmacokinetics of gabapentin hydrochloride has been studied in healthy volunteers and patients with epilepsy. Gabapentin bioavailability is dose-dependent, decreasing from an average of about 60% at a 300 mg dose to about. 35% or less at doses used to treat neuropathic pain. Tile underlying mechanism responsible for this dose-dependence is belie ved to be saturable absorption of gabapentin from the intestine of h umans and animals by a low capacity, solute transporter localized in die upper small intestine.

[0023 I.J Following oral absorption, gabapentin is excreted in the urine without significant metabolism. The plasma half-life of gabapentin in humans is relatively short (5 - 7 hours), necessitating administration three or four times per day . It has been shown that dosing regimens requiring three or four doses per day can lead to significant noncompliance in patients with epilepsy. Patients who experience sleep interference from their underlying symptoms may be inadequately treated if the eftect of a bedtime dose of gabapentin does not last through the night. A more prolonged, stable exposure to gabapentin may provide several clinical benefits, including greater efficacy, prolonged duration of action, and a reduced incidence of adverse effects related to peak drag levels. However, it has not been possible to achieve this with a sustained release formulation of gabapentin. due to the lack of significant absorption in the large intestine. } 0 232 Evaluation of Pharmacokinetic parameters of the illustrative compounds versus gabapentin HCI

Oral Bioavailability, Sprague-Dawley male rats (6 rats/group) received the following treatments by oral gavage: gabapentin HCI salt at 100 mg-eq GP/kg and molecular equivalent or stoichiometric ratio equivalent dosage of gabapentin of the Formula I prodrug free acid. Administration of the compounds to six male rats by oral gavage at 100 mg-eq GP/kg and equivalent dosage/kg form of Formula 1 (1 -1 ). Blood samples were obtained at intervals over post-dosing. Ail plasma samples were subsequently analyzed for intact prodrug (Formula I ( 1-1)), were analyzed using LC/MS MS.

|00233| Oral Bioavailabilit in Rats

Pharmacokinetic parameters for gabapentin HCI and Formiila i ( 1-1 ) in free acid form as gabapentin analyte following administration to rats.

|00234| The term "sample" refers to a sample of a body fluid, to a sample of separated cells or to a sample from a tissue or an organ. Samples of body fluids can be obtained by well known techniques and include, preferably, samples of blood, plasma, serum, or urine, more preferably, samples of blood, plasma or serum. ^'Tissue or organ samples may be obtained from any tissue or organ by, e.g., biopsy. Separated cells may be obtained from the body fluids or the tissues or organs by separating techniques such as centrifugation or cell sorting. Preferably, cell-, tissue- or organ samples are obtained from those cells, tissues or organs which express or produce the peptides referred to herein. 002351 EQUIVALENTS

The present disclosure provides among other things compositions and methods for treating metabolic conditions or neurodegenerative disorders and their complications. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the claimed systems and methods should be determined by reference to the claims, along with their full scope of equivalents, and the specification., along with such variations, 002361 INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to he incorporated by reference. l.n case of conflict, the present application, including any definitions herein, will control.

Claims

CLAIMS:

A pharmaceutical composition comprising a compound of Formula I

Formula I

and a pharmaceutically acceptable salt, hydrate, solvate, prodrug, enaniiomer, and stereoisomer thereof;

Wherein

R^l is independently selected from the group consisting of hydrogen, methyl, amine, carboxyl, hydroxy., (S -butane-l,2-diol, 2-hydroxy acetamide, cycohexyl methyl ether, butox , propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyl,

R^* each independentl represents

each a is independently 5 or 6;

each b is independently 2 or 3,

2. The compound of claim 1 , wherein the compound is a molecular conjugate of gabapentin and omega- fatty acid.

3. The compound of claim .1. wherein the compound is a molecular conjugate of gabapentin and thioctic acid.

4. A pharmaceutical composition comprising a compound of Formula II,

Formula Π

and pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, and stereoi sorrier thereof;

Wherein

R^! is independently selected from the group consisting of hydrogen, methyl, amine, carboxyl, hydroxy!, (S)~butarte-.i ,2~dioi, 2 -hydroxy acetamide, cycohexyl methyl ether, butoxy, propoxy, thiol, alkyi, alkyi thiol, acetyl thiol, disulfide, acy!,

each a is independently 5 or 6;

each b is independently 2 or 3.

5 , The compound of claim 4, wherein the compound is a molecular conjugate of pfegabalin and omcga-3 fatt acid.

6. The compound of claim 4, wherein the compound is a molecular conjugate of pregabalin and thioctic acid. pharmaceutical composition comprising a compound of formula 111,

R

Formula HI

and pharmaceutically acceptable salt, hydrate, solvate, prodrug, enantiomer, and stereoisomer thereof;

f is independently selected from the group consisting of hydrogen, methyl amine, carboxyl, hydroxy!, (S)-butane-l.,2-diol, 2-hydroxy aeetamide, eycohexyi methyl ether, butoxy, propoxy, thiol, alkyi, alkyi thiol, acetyl thiol, dssuifide, acyl,

R² each independently represents

each a is independently 5 or 6;

each b is independently 2 or 3,

8. The compound of claim 7. wherein the compound is a molecular conjugate of phenibut and oraega-3 fatty acid.

9. The compound of claim 7, wherein the compound is a molecular conjugate of phenibut and thioctic acid,

10. A pharmaceutical composition comprising a compound of Formula I V,

Formula IV

and pharmaceutically acceptable salt, hydrate, solvate, prodaig, enantiomer, and siereoi som er th ereof ,

R^f is independently selected from the group consisting of hydrogen, methyl amine, carboxyi. hydrox h (S)-butane-l,2-dioi, 2-hydroxy aeetamide, cycohexy! methyl ether, butoxy, propoxy, thiol, alkyl, alkyl thiol, acetyl thiol, disulfide, acyi.

8S

R² each independent]}? represents

each a is independently 5 or 6;

each b is independently 2 or 3.

1 1. The compound of claim 10, wherein the compound is a molectiiar conjugate of ptcamiion and oinega-3 fatty acid.

12. The compound of claim 10, wherein the compound is a molecular conjugate of picainiion and thioclk acid.

13. Compounds and compositions of formula Ϊ in claim 1 are formulated for the treatment of neurological disease and condiiioos such as neuropathic pain, epilepsy, restless leg syndrome, diabetic neuropathic pain and other diseases related sub- chronic and chronic pain.

1 . Compounds and compositions of formula 11 in claim 4 are formulated for the treatment: of neurological disease and conditions such as neuropathic pain, epilepsy, restless leg syndrome, diabetic neuropathic pain and other diseases related sub- chronic and chronic pain.

15. Compounds and compositions of formula 0Ϊ in ciaim 7 arc formulated for the treatment of neurological disease and conditions such as neuropathic pain, epilepsy, restless leg syndrome, diabetic neuropathic pain and other diseases related sub- chronic and chronic pain.

16. Compounds and compositions of formula IV in claim 10 are formulated for the treatmeat of neurological disease and conditions such as neuropathic pain, epilepsy, restless leg syndrome, diabetic neuropathic pain and other diseases related sub-chronic and chronic pai .