WO2012121862A2 - Composés dérivés de l'acide valproïque - Google Patents

Composés dérivés de l'acide valproïque Download PDF

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WO2012121862A2
WO2012121862A2 PCT/US2012/025627 US2012025627W WO2012121862A2 WO 2012121862 A2 WO2012121862 A2 WO 2012121862A2 US 2012025627 W US2012025627 W US 2012025627W WO 2012121862 A2 WO2012121862 A2 WO 2012121862A2
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Prior art keywords
dextran
compound
subject
conjugate
alkyl
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PCT/US2012/025627
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WO2012121862A3 (fr
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A. M. Mahbub HASSAN
Guenther Hochhaus
Paul R. Carney
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University Of Florida Research Foundation
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Publication of WO2012121862A3 publication Critical patent/WO2012121862A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/02—Dextran; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/11—Compounds covalently bound to a solid support

Definitions

  • Epilepsy is a neurological disease that is characterized by paroxysmal transient disturbances of the electrical activity of the brain. Epileptic seizures may be partial or focal seizures that are restricted to a particular locus within the brain, or generalized seizures which can result in abnormal activity throughout the brain [1]. Epilepsy is the most frequent neurodegenerative disease after stroke. It afflicts more than 2 million Americans and 50 million people worldwide [2]. Temporal lobe epilepsy (TLE), where seizures originate from the temporal lobe of the brain [3], is among the most frequent types of drug-resistant epilepsy. Individuals affected with TLE typically have an initial precipitating injury (IPI) such as the status epilepticus (SE), head trauma, encephalitis or childhood febrile seizures [4-6].
  • IPI initial precipitating injury
  • This invention provides a pro-drug of valproic acid, valproic acid conjugated to dextran, which will release the active drug slowly in vivo by hydrolysis and hence, prolong its effect.
  • Dextrans are glucose polymers which have been used for more than 50 years as plasma volume expanders. Dextrans contain a large number of hydroxyl groups which can be easily conjugated to valproic acid by either direct attachment or, through a linker [13-15].
  • an intra- cerebroventricular (ICV) injection of pro-drug of VPA will require lower amount of conjugate to achieve therapeutic level in cerebrospinal fluid (CSF), minimizing fluctuation in therapeutic level, will have minimum blood level of active drug and will have less incidence of adverse effects. Also, this prolonged release formulation will avoid multiple daily administrations and was very suitable for preventing
  • This invention provides for delivering the dextran valeric acid conjugate to the relevant area of the brain, and provides a slow release of the active principle through chemical hydrolysis.
  • One aspect is a compound of formula (I) or salt thereof, solvate or hydrate thereof:
  • L is a bond; -O-alkyl-; -O-alkyl-C(O)-; -O-alkyl-O-C(O)-; -O-alkoxy-, -O- alkoxy-C(O)-; or -O-alkoxy-O-C(O)-; and DEX is a dextran; wherein in each alkyl group one or more -CH 2 - groups can optionally be replaced with an -O- group.
  • One aspect is a compound of formula (I) or salt thereof, solvate or hydrate thereof:
  • L is a bond, -O-alkyl-, -O-alkyl-C(O)-; or -O-alkyl-O-C(O)-; and DEX is a dextran.
  • L is a bond
  • the dextran is a l,000Da to 150,000Da dextran
  • the dextran is a l,000Da to 100,000Da dextran
  • the dextran is a 10,000Da to 150,000Da dextran
  • the dextran is a 10,000Da to 100,000Da dextran
  • dextran is a 70,000Da dextran
  • dextran is a 10,000Da dextran or
  • dextran is a l,000Da dextran.
  • composition comprising a compound of formula (I) or salt thereof, solvate or hydrate thereof:
  • L is a bond; -O-alkyl-; -O-alkyl-C(O)-; -O-alkyl-O-C(O)-; -O-alkoxy-, -O- alkoxy-C(O)-; or -O-alkoxy-O-C(O)-; and DEX is a dextran; wherein in each alkyl group one or more -CH 2 - groups can optionally be replaced with an -O- group.
  • composition comprising a compound of formula (I) or salt thereof, solvate or hydrate thereof:
  • L is a bond, -O-alkyl-, -O-alkyl-C(O)-; or -O-alkyl-O-C(O)-; and DEX is a dextran.
  • DEX is a dextran.
  • L is a bond
  • the dextran is a l,000Da to 150,000Da dextran
  • the dextran is a l.OOODa to 100,000Da dextran
  • the dextran is a 10,000Da to 150,000Da dextran
  • the dextran is a 10,000Da to 100,000Da dextran
  • dextran is a 70,000Da dextran
  • dextran is a 10,000Da dextran
  • dextran is a l,000Da dextran
  • degree of substitution is between 0.10 and 0.90 mole fraction
  • degree of substitution is between 0.10 and 0.50 mole fraction
  • the invention provides a method of treating a subject suffering from or susceptible to brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • the method includes administering to a subject in need thereof a therapeutically effective amount of a valproic acid:dextran compound (e.g., a compound herein).
  • the invention provides a method of treating a subject having brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • the method includes administering to a subject identified as in need thereof a therapeutically effective amount of a valproic acid dextran compound or composition thereof.
  • the invention provides a method of treating a subject suffering from or susceptible to brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, comprising administering to the subject an effective amount of a valproic acid:dextran compound (e.g., a compound herein) or
  • composition thereof such that the subject is treated.
  • the invention provides a method of treating a subject suffering from or susceptible to a disorder comprising administering to subject in need thereof a therapeutically effective amount of a compound herein or composition thereof.
  • the invention provides a packaged composition including a therapeutically effective amount of a valproic acid:dextran compound and a pharmaceutically acceptable carrier or diluent.
  • the composition may be formulated for treating a subject suffering from or susceptible to brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, and packaged with instructions to treat a subject suffering from or susceptible to brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • the invention provides a kit for treating brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof in a subject is provided and includes a compound herein, a pharmaceutically acceptable esters, salts, and prodrugs thereof, and instructions for use.
  • FIG 1. depicts a first order plot of hydrolysis of VPA-D 10 conjugate in phosphate buffer.
  • FIG 2. depicts a zero order plot of hydrolysis of VPA-D 10 conjugate in phosphate buffer.
  • FIG 3. depicts a first order plot of hydrolysis of VPA-D 10 conjugate in NaHC0 3 /Na 2 C0 3 buffer.
  • FIG 4. depicts a zero order plot of hydrolysis of VPA-D 10 conjugate in NaHC0 3 /Na 2 C0 3 buffer.
  • FIG 5. depicts a first order plot of hydrolysis of VPA-D70 conjugate in phosphate buffer.
  • FIG 6. depicts a zero order plot of hydrolysis of VPA-D70 conjugate in phosphate buffer.
  • FIG 7. depicts a first order plot of hydrolysis of VPA-D70 conjugate in NaHC0 3 /Na 2 C0 3 buffer.
  • FIG 8. depicts a zero order plot of hydrolysis of VPA-D70 conjugate in
  • FIG 9. depicts hydrolysis of conjugate VPA-TEG-D1 in different media.
  • FIG 10. depicts hydrolysis of conjugate VPA-PEG-D1 in different media.
  • administration includes routes of introducing the compound of the invention(s) to a subject to perform their intended function.
  • routes of administration include injection
  • the pharmaceutical preparations may be given by forms suitable for each administration route.
  • these preparations are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories.
  • Oral administration is preferred.
  • the injection can be bolus or can be continuous infusion.
  • the compound of the invention can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function.
  • the compound of the invention can be administered alone, or in conjunction with either another agent as described above or with a pharmaceutically- acceptable carrier, or both.
  • the compound of the invention can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent.
  • the compound of the invention can also be administered in a pro-drug form which is converted into its active metabolite, or more active metabolite in vivo.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • heteroalkyl further includes alkyl groups, which can further include oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorous atoms.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C 3 -C 30 for branched chain), preferably 26 or fewer, and more preferably 20 or fewer, and still more preferably 4 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons in the ring structure.
  • alkyl as used throughout the specification and sentences is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoro
  • alkylaryl is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • alkyl also includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six, and still more preferably from one to four carbon atoms in its backbone structure, which may be straight or branched-chain.
  • lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl, heptyl, octyl and so forth.
  • the term "lower alkyl” includes a straight chain alkyl having 4 or fewer carbon atoms in its backbone, e.g., C1-C4 alkyl.
  • alkoxy refers to an -O-alkyl radical, wherein the alkyl group may optionally have one or more additional -O- atoms in place of any -CH 2 - group in the alkyl chain.
  • alkoxyalkyl refers to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the invention contemplates cyano and propargyl groups.
  • aryl refers to the radical of aryl groups, including 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like. Those aryl groups having
  • heteroatoms in the ring structure may also be referred to as "aryl heterocycles,"
  • heteroaryls or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulf
  • association refers to a condition of proximity between a chemical entity or compound, or portions thereof, and a binding pocket or binding site on a protein.
  • the association may be non-covalent (wherein the juxtaposition is energetically favored by hydrogen bonding or van der Waals or electrostatic interactions) or it may be covalent.
  • binding pocket refers to a region of a molecule or molecular complex, that, as a result of its shape, favorably associates with another chemical entity or compound.
  • biological activities of a compound of the invention includes all activities elicited by compound of the inventions in a responsive cell. It includes genomic and non-genomic activities elicited by these compounds.
  • Bio composition refers to a composition containing or derived from cells or biopolymers.
  • Cell-containing compositions include, for example, mammalian blood, red cell concentrates, platelet concentrates, leukocyte concentrates, blood cell proteins, blood plasma, platelet-rich plasma, a plasma concentrate, a precipitate from any fractionation of the plasma, a supernatant from any fractionation of the plasma, blood plasma protein fractions, purified or partially purified blood proteins or other components, serum, semen, mammalian colostrum, milk, saliva, placental extracts, a cryoprecipitate, a cryo supernatant, a cell lysate, mammalian cell culture or culture medium, products of fermentation, ascites fluid, proteins induced in blood cells, and products produced in cell culture by normal or transformed cells (e.g., via recombinant DNA or monoclonal antibody technology).
  • Biological compositions can be cell-free.
  • a suitable biological composition or biological sample is a red blood cell suspension.
  • the blood cell suspension includes mammalian blood cells.
  • the blood cells are obtained from a human, a non-human primate, a dog, a cat, a horse, a cow, a goat, a sheep or a pig.
  • the term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • diastereomers refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
  • an effective amount includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to treat a treating brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • An effective amount of compound of the invention may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound of the invention to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response.
  • An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the compound of the invention are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount of compound of the invention may range from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • an effective dosage may range from about 0.001 to 30 mg/kg body weight, preferably about 0.01 to 25 mg/kg body weight, more preferably about 0.1 to 20 mg/kg body weight, and even more preferably about 1 to 10 mg/kg, 2 to 9 mg/kg, 3 to 8 mg/kg, 4 to 7 mg/kg, or 5 to 6 mg/kg body weight.
  • the skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present.
  • treatment of a subject with a therapeutically effective amount of a compound of the invention can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with a compound of the invention in the range of between about 0.1 to 20 mg/kg body weight, one time per week for between about 1 to 10 weeks, preferably between 2 to 8 weeks, more preferably between about 3 to 7 weeks, and even more preferably for about 4, 5, or 6 weeks.
  • the effective dosage of a compound of the invention used for treatment may increase or decrease over the course of a particular treatment.
  • the term "enantiomers" refers to two stereoisomers of a compound which are non-superimposable mirror images of one another. An equimolar mixture of two enantiomers is called a "racemic mixture" or a "racemate.”
  • haloalkyl is intended to include alkyl groups as defined above that are mono-, di- or polysubstituted by halogen, e.g., fluoromethyl and trifluoromethyl.
  • halogen designates -F, -CI, -Br or -I.
  • hydroxyl means -OH.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • homeostasis is art-recognized to mean maintenance of static, or constant, conditions in an internal environment.
  • improved biological properties refers to any activity inherent in a compound of the invention that enhances its effectiveness in vivo. In a preferred embodiment, this term refers to any qualitative or quantitative improved therapeutic property of a compound of the invention, such as reduced toxicity.
  • optional substituents include, for example, hydroxy, halogen, cyano, nitro, CrCgalkyl, C 2 -C8 alkenyl, C 2 -Cgalkynyl, C - Cgalkoxy, C 2 -Cgalkyl ether, C3-Cgalkanone, CrCgalkylthio, amino, mono- or di-(Cl- Cgalkyl)amino, haloCrCgalkyl, haloCrCgalkoxy, CrCgalkanoyl, C 2 -Cgalkanoyloxy, Ci-Cgalkoxycarbonyl, -COOH, -CONH 2 , mono- or di-(Ci -Cgalkyl)aminocarbonyl, - S0
  • substitution is also indicated by the phrase "substituted with from 0 to X substituents," where X is the maximum number of possible substituents.
  • Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substituents).
  • the term “isomers” or “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical
  • administration usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • polycyclyl or “polycyclic radical” refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl,
  • prodrug or "pro-drug” includes compounds with moieties that can be metabolized in vivo.
  • the prodrugs are metabolized in vivo by esterases or by other mechanisms to active drugs.
  • Examples of prodrugs and their uses are well known in the art (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19).
  • the prodrugs can be prepared in situ during the final isolation and purification of the compounds, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted into esters via treatment with a carboxylic acid.
  • prodrug moieties include substituted and unsubstituted, branch or unbranched lower alkyl ester moieties, (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g. , acetyloxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., propionoic acid esters), lower alkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.
  • prodrug moieties are propionoic acid esters and acyl esters.
  • Prodrugs which are converted to active forms through other mechanisms in vivo are also included.
  • a prophylactically effective amount of a compound refers to an amount of a compound of the invention any formula herein or otherwise described herein which is effective, upon single or multiple dose administration to the patient, in preventing or treating disease, e.g., treating brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • reduced toxicity is intended to include a reduction in any undesired side effect elicited by a compound of the invention when administered in vivo.
  • sulfhydryl or "thiol” means -SH.
  • subject includes organisms which are capable of suffering from a cell a disease or disorder or who could otherwise benefit from the administration of a compound of the invention of the invention, such as human and non-human animals.
  • Preferred humans include human patients suffering from or prone to suffering from brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof or associated state, as described herein.
  • non-human animals of the invention includes all vertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals, such as non-human primates, sheep, dogs, cats, cows, chickens, amphibians, reptiles, etc.
  • seisusceptible to epilepsy, seizures or ocular diseases, disorders or symptoms thereof is meant to include subjects at risk of developing epilepsy, seizures or ocular diseases, disorders or symptoms thereof, or subjects having a family or medical history of treating brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, and the like.
  • peripheral administration and “administered peripherally” as used herein mean the administration of a compound of the invention(s), drug or other material, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • terapéuticaally effective amount of a compound of the invention of the invention refers to an amount of an agent which is effective, upon single or multiple dose administration to the patient, in treating brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • the invention provides compounds that are dextran derivatives of valproic acid (also known as 2-propylpentanoic acid), including those delineated in any of the formulae herein.
  • valproic acid also known as 2-propylpentanoic acid
  • the compounds are also depicted as those of formula I:
  • L is a bond, -O-alkyl-, -, -O-alkyl-C(O)-; or -O-alkyl-O-C(O)-; and DEX is a dextran of molecular weight between about lkD and 150 kD, in an alternate embodiment between about lOkD and 150kD.
  • the valproic acid:dextran conjugate is of the formula below where the conjugate is a dextran of molecular weight between lkD and 150 kD, in an alternate embodiment between about lOkD and 150kD that is attached via the 4-position oxygen (glucose numbering) Valproic acid-Dextran conjugate wherein the darker squiggly bonds indicate attachment to the dextran chain of the appropriate molecular weight range (e.g., between lkD and 150kD; lOkD and
  • Certain preferred compounds include compounds specifically delineated herein:
  • Valproic acid dextran conjugate [lOkD MW) [VPA-D-10];
  • Valproic acid dextran conjugate [70kD MW) [VPA-D-70];
  • Valproic acid -triethylene glycol-dextran conjugate [VPA-TEG-D-1];
  • Valproic acid -pentaethylene glycol-dextran conjugate [VPA-PEG-D- i];
  • the invention also relates to the pharmaceutically acceptable salts and esters of the above-mentioned compounds.
  • Naturally occurring or synthetic isomers can be separated in several ways known in the art. Methods for separating a racemic mixture of two enantiomers include chromatography using a chiral stationary phase (see, e.g., "Chiral Liquid Chromatography,” W.J. Lough, Ed. Chapman and Hall, New York (1989)).
  • Enantiomers can also be separated by classical resolution techniques. For example, formation of diastereomeric salts and fractional crystallization can be used to separate enantiomers. For the separation of enantiomers of carboxylic acids, the
  • diastereomeric salts can be formed by addition of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like.
  • diastereomeric esters can be formed with enantiomerically pure chiral alcohols such as menthol, followed by separation of the diastereomeric esters and hydrolysis to yield the free, enantiomerically enriched carboxylic acid.
  • enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like.
  • diastereomeric esters can be formed with enantiomerically pure chiral alcohols such as menthol, followed by separation of the diastereomeric esters and hydrolysis to yield the free, enantiomerically enriched carboxylic acid.
  • chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or
  • Another object of the present invention is the use of a compound as described herein (e.g., of any formulae herein) in the manufacture of a medicament for use in the treatment of a disorder or disease (e.g., brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof).
  • a disorder or disease e.g., brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • a compound as described herein e.g., of any formulae herein
  • for use in the treatment of a disorder or disease e.g., brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • Another aspect is a compound made by any of the processes described herein
  • the compounds delineated herein are useful in methods for modulating disease and disorders and symptoms thereof, particularly those where valproic acid is indicated.
  • Such conditions include for example, brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • the invention provides a method of treating brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof in a subject comprising administering to the subject identified as in need thereof a compound that is any compound delineated herein, or composition thereof.
  • the methods of the invention include administering to a subject a therapeutically effective amount of a compound of the invention in combination with another pharmaceutically active compound.
  • pharmaceutically active compounds include compounds known to treat brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, e.g., brain trauma agent, antiepileptic agent, antiseizure agent, ocular disease agent.
  • Other pharmaceutically active compounds that may be used can be found in Harrison's Principles of Internal Medicine, Thirteenth Edition, Eds. T.R. Harrison et al.
  • the compound of the invention and the pharmaceutically active compound may be administered to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).
  • the therapeutically effective amount or dose, and the prophylactically effective amount or dose a number of factors are considered by the attending clinician, including, but not limited to: the specific brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof involved; pharmacodynamic characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the kind of concurrent treatment (i.e., the interaction of the compound of the invention with other co-administered therapeutics); and other relevant circumstances.
  • the attending clinician including, but not limited to: the specific brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof involved; pharmacodynamic characteristics of the particular agent and its mode and route of administration; the desired time course of treatment; the species of mammal; its size, age
  • Treatment can be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • a therapeutically effective amount and a prophylactically effective amount of a compound of the invention of the invention is expected to vary from about 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day.
  • Compounds determined to be effective for the prevention or treatment of brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof in animals may also be useful in treatment of in humans.
  • animals e.g., mammals, primates, dogs, chickens, and rodents
  • Those skilled in the art of treating brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof in humans will know, based upon the data obtained in animal studies, the dosage and route of administration of the compound to humans. In general, the dosage and route of administration in humans is expected to be similar to that in animals.
  • a method of assessing the efficacy of a treatment in a subject includes determining the pre-treatment extent of brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof by methods well known in the art and then administering a therapeutically effective amount valproic acid dextran compound (e.g., those described herein) according to the invention to the subject. After an appropriate period of time after the administration of the compound (e.g., 1 day, 1 week, 2 weeks, one month, six months), the extent of the brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof is determined again.
  • a therapeutically effective amount valproic acid dextran compound e.g., those described herein
  • the modulation (e.g., decrease) of the extent or invasiveness of the brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof indicates efficacy of the treatment.
  • the extent or invasiveness of the brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof may be determined periodically throughout treatment. For example, the extent or invasiveness of the brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof may be checked every few hours, days or weeks to assess the further efficacy of the treatment.
  • a decrease in extent or invasiveness of the brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof indicates that the treatment is efficacious.
  • the method described may be used to screen or select patients that may benefit from treatment with a compound herein.
  • obtaining a biological sample from a subject includes obtaining a sample for use in the methods described herein.
  • a biological sample is described above.
  • a compound of the invention is packaged in a
  • composition may be formulated for treating a subject suffering from or susceptible to brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, and packaged with instructions to treat a subject suffering from or susceptible to brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • methods of inhibiting a brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof in a subject include administering an effective amount of a compound of the invention (i.e., a compound described herein) to the subject.
  • the administration may be by any route of administering known in the pharmaceutical arts.
  • the subject may have brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, may be at risk of developing brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, or may need prophylactic treatment prior to anticipated or unanticipated exposure to one or more conditions capable of increasing susceptibility to a brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • a method of monitoring the progress of a subject being treated with a compound herein includes determining the pre-treatment status of the brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, administering a therapeutically effective amount of a compound herein to the subject, and determining the status of the brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof after an initial period of treatment with the compound, wherein the modulation of the status indicates efficacy of the treatment.
  • the subject may be at risk of brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof , may be exhibiting symptoms of brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof, may be susceptible to brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof and/or may have been diagnosed with brain trauma, epilepsy, seizures or ocular diseases, disorders or symptoms thereof.
  • the subject may be treated with the compound.
  • the subject can be administered therapeutically effective dose or doses of the compound.
  • Kits of the invention include kits for treating brain trauma, epilepsy, seizures and ocular diseases, disorders or symptoms thereof in a subject.
  • the kit may include a compound of the invention, for example, a compound described herein,
  • kits may also include, reagents, for example, test compounds, buffers, media (e.g., cell growth media), cells, etc.
  • Test compounds may include known compounds or newly discovered compounds, for example, combinatorial libraries of compounds.
  • One or more of the kits of the invention may be packaged together, for example, a kit for assessing the efficacy of a treatment for brain trauma, epilepsy, seizures and ocular diseases, disorders or symptoms thereof, or may be packaged with a kit for monitoring the progress of a subject being treated for brain trauma, epilepsy, seizures and ocular diseases, disorders or symptoms thereof according to the invention.
  • the invention also provides a pharmaceutical composition, comprising an effective amount of a compound of the and a pharmaceutically acceptable carrier.
  • the effective amount is effective to treat a disease, disorder, or symptom thereof as described previously.
  • the compound of the invention is administered to the subject using a pharmaceutically- acceptable formulation, e.g., a pharmaceutically- acceptable formulation that provides sustained delivery of the compound of the invention to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • a pharmaceutically- acceptable formulation e.g., a pharmaceutically- acceptable formulation that provides sustained delivery of the compound of the invention to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • these pharmaceutical compositions are suitable for topical or oral administration to a subject.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • phrases "pharmaceutically acceptable” refers to those compound of the inventions of the present invention, compositions containing such compounds, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier includes pharmaceutically- acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier is “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can 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 carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • compositions containing a compound of the invention(s) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, more preferably from about 10 per cent to about 30 per cent.
  • compositions include the step of bringing into association a compound of the invention(s) with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in- 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) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the invention(s) as an active ingredient.
  • a compound may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically- acceptable carriers, such as sodium citrate or dicalcium phosphate, 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, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic 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,
  • 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 such excipients as lactose or milk sugars, as well as high molecular weight
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or
  • compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compound of the invention(s) include pharmaceutically- acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solub
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compound of the invention(s) may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of the invention for rectal or vaginal for rectal or vaginal
  • compositions of the present invention 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 appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of the invention(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound of the invention(s) may be mixed under sterile conditions with a pharmaceutically- acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to compound of the invention(s) of the present invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of the
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the compound of the invention(s) can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a nonaqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically-acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention(s) to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active ingredient in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of the invention.
  • compositions of the invention suitable for parenteral administration comprise one or more compound of the invention(s) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous 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, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (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.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can 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.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of compound of the invention(s) in biodegradable polymers such as polylactide- polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compound of the invention(s) When the compound of the invention(s) are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically- acceptable carrier.
  • the compound of the invention(s) which may be used in a suitable hydrated form, and/or the
  • compositions of the present invention are formulated into
  • Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • An exemplary dose range is from 0.1 to 10 mg per day.
  • a preferred dose of the compound of the invention for the present invention is the maximum that a patient can tolerate and not develop serious side effects.
  • the compound of the invention of the present invention is administered at a concentration of about 0.001 mg to about 100 mg per kilogram of body weight, about 0.001 - about 10 mg/kg or about 0.001 mg - about 100 mg/kg of body weight. Ranges intermediate to the above-recited values are also intended to be part of the invention.
  • ⁇ -NMR spectra was obtained from a Bruker, Avance II 600 Spectrometer with 5 mm TXI CryoProbe sample head, operating at 600 MHz.
  • the sample tube size is 5 mm with a sample concentrations of 50 mg/0.5 ml for valproic acid, 10 mg/0.5 ml for the dextran 10 000, 7 mg/0.5 ml for the dextran 70 000 as control substances, 16 mg/0.5 ml for conjugate D-70-II and 20 mg/0.5 ml for conjugate D-10-II.
  • DMSO-d 6 was used as a solvent. The samples was measured at 40°C.
  • There was also one band around ⁇ 12 for the organic acid group, which was very small in case of the NMR chromatograms of the conjugates.
  • aqueous solubility of valproic acid-dextran conjugate To determine aqueous solubility of the conjugate at 25 °C, approximately 50 mg of conjugate was added to 1.5 ml of double distilled water. The mixture will then be sonicated for 60 minutes to dissolve as much conjugate as possible and afterwards it was centrifuged for 10 minutes at 13,200 rpm to precipitate the un-dissolved conjugate. Then, 1ml of the supernatant was added to 10 ml of NaOH solution (0.5 N), to perform complete hydrolysis. At different time points, 500 ⁇ of each sample was collected into 1 ml HPLC vials and 500 ⁇ of HCl solution (0.5 N) was added to each vial to neutralize the base [17]. The experiment was done in triplicate. The samples thus prepared was stored in the refrigerator before being analyzed by HPLC.
  • a portion of conjugate was dissolved in 50 ml of buffer solutions (0.1 M). Three different buffer solutions was used for 3 different pH- Citric Acid/Na 2 HP0 4 buffer (pH 5.0), Phosphate buffer (pH 7.5) and NaHC0 3 /Na 2 C0 3 buffer (pH 10.22)
  • pH- Citric Acid/Na 2 HP0 4 buffer pH 5.0
  • Phosphate buffer pH 7.5
  • NaHC0 3 /Na 2 C0 3 buffer pH 10.22
  • the hydrolysis study was carried out at 37 °C and at 47 °C in an incubator under continuous stirring of the samples. Samples of 1 ml was collected at predetermined time intervals and 1 ml of buffer solution was added to the samples to keep the volume constant [15, 17, 21]. The experiment was done in triplicate. All samples was kept in the freezer at -20 °C before being analyzed by HPLC. See FIGs. 1-8.
  • the conjugate showed negligible, or no hydrolysis in acidic medium (p 5.0).
  • the primary objective of this aim is to synthesize valproic acid-dextran conjugate having a spacer in between to make the bond formed between VPA and linker more accessible by the esterase enzyme and to study in vitro hydrolysis of the conjugate in the presence of esterase enzyme. Also, study of in vitro hydrolysis of the conjugate formed by direct attachment of VPA to dextran in the presence of esterase enzyme to determine the nature and extent of the effect of enzyme on the rate of hydrolysis of this type of conjugate is performed. [23-25]. Macromolecular pro-drugs synthesized by direct attachment of drug to the dextran appeared to be stable towards enzymatic cleavage by various esterase enzymes.
  • Porcine liver esterase Hydrolysis of valproic acid-dextran conjugate (with and without the linker in between) is studied in the presence of porcine liver esterase. Porcine liver esterase is used for the study, because of its stability, low cost and the ability to hydrolyze a wide range of substrates without the need for co-enzymes.
  • a 0.001 M stock solution of both conjugates is prepared in de-ionized double-distilled water. At the beginning of each experiment, the stock solution is diluted with 0.15 M phosphate-buffered saline
  • PBS PBS
  • the solutions are then diluted to one of five final concentrations by the addition of PBS: 1, 50, 100, 150 and 200 ⁇ [21].
  • controls are prepared by repeating the dilutions described above without the addition of the esterase solution.
  • the solutions are placed in an incubator at 37 °C and are agitated by magnetic stirring bars throughout the experiment. Over a period of 30 minutes to 48 hours, aliquots of 500 ⁇ L ⁇ are removed periodically and added to Eppendorf vials containing an equal volume of acetonitrile to quench enzyme-catalyzed reaction.
  • the samples are centrifuged at 10,500g for 10 minutes and after that 500 ⁇ ⁇ aliquots of the supernatant are removed and added to glass auto-sampler vials and stored at -20 °C prior to analysis by HPLC [28].
  • Stability of porcine liver esterase- Esterase from porcine liver is available as lyophilized powder (Sigma- Aldrich) and should be stored at -20 °C for maximum stability. All samples with enzymes are prepared on the day of experiment and stored at temperatures of 0-4 °C (on ice-bath) prior to the experiment. The samples are allowed to equilibrate in screw-capped bottles for one hour at 37 °C, before the addition of pro-drug solution. All enzyme preparations are kept for no more than 50 hours [29] . However, the suitable conditions for carrying out the experiment (for optimal activity) and for storage (for stability) of the enzyme should be reevaluated based on the supplier's specification.
  • Protocol for the synthesis of VPA-linker-Dextran conjugate Two conjugates of valproic acid were synthesized according to the following protocol. Two different linkers were used for the two conjugates. These are- triethylene glycol (TEG) and pentaethylene glycol (PEG). We used dextrans with molecular weights about 1 KDa.
  • TEG triethylene glycol
  • PEG pentaethylene glycol
  • conjugate solution 1 ml of the conjugate solution and 5 ml of ethyl acetate will be transferred in a centrifugal tube to make sure that conjugate is precipitated. If conjugate precipitates, then around 6 ml of conjugate solution will be transferred in 4 centrifugal tubes and around 30 ml of ethyl acetate will be added to each of them. Then the mixtures will be centrifuged at 2500 rpm for 5 minutes. After that the supernatant will be discarded and the conjugate will be dissolved in 6 ml DMSO (each tube) with the homogenizer.
  • 6 ml DMSO each tube
  • Conj-1-1 16.1 mg Conj-1-2: 11.7 mg Conj-1-3: 19.6 mg
  • HCL 0.5 N will be added to each vial to neutralize the base.
  • the collected samples will then be analyzed for drug content by HPLC analysis.
  • Protocol for enzymatic hydrolysis study of the coniugates VPA-linker-Dl Enzyme solution-I Take 7 ml of IX PBS solution (p w 7.4, 0.01 M) in a small glass vial at room temperature. Then, weigh about 17 mg (approx.
  • NTPSE National General Practice Study of Epilepsy

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Abstract

L'invention concerne des composés acide valproïque:dextran et des procédés pour les utiliser. L'invention concerne en outre des compositions pharmaceutiques et des procédés de traitement de diverses maladies et troubles, notamment un trauma cérébral, l'épilepsie, des crises épileptiques et des maladies oculaires et leurs troubles ou leurs symptômes.
PCT/US2012/025627 2011-02-17 2012-02-17 Composés dérivés de l'acide valproïque WO2012121862A2 (fr)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2015168614A3 (fr) * 2014-05-01 2015-12-30 Board Of Regents Of The University Of Nebraska Compositions polymères d'inhibiteurs de l'histone déacétylase et leurs méthodes d'utilisation

Citations (3)

* Cited by examiner, † Cited by third party
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