Patent Application: US-201514792654-A

Abstract:
the low steroid hormone levels of neutered or aging mammals is associated with a dramatic increase in risk of cancer . this invention pertains to a natural method of replenishing the low steroid hormone levels of neutered or aging mammals , levels that are associated with high cancer risk , to levels of those of non - neutered or young animals , levels that are associated with a low cancer risk . the invention also pertains to methods of maintaining healthy levels of several important natural metabolites that can become depleted during the steroid hormone replenishment process .

Description:
a preferred embodiment of the invention is a pharmaceutical composition of dhea in sufficient amount to induce egss , thereby reconstituting normal or near normal steroid hormone levels in neutered animals , and sufficient bh4 , ipa , potassium nitrate ( or similar nitric oxide donor ), folinic acid ( or purines , pyrimidines , same ), monoamine precursors and cofactors , and ubiquinone and / or tocotrienol to maintain or reconstitute normal or near normal levels of , respectively , bh4 , ipa , nitric oxide , one carbon pool metabolites , monoamine precursors and cofactors , and ubiquinone , thereby preventing the negative side effects of egss . to effect egss and restore steroid hormones to normal or near normal levels , dhea or its congeners can be administered at a dose of , preferentially , from about 0 . 1 to 50 mg / kg ; more preferentially 0 . 5 to 30 mg / kg ; and most preferentially 1 to 10 mg / kg . dhea , dheas , dhea sulfatide and any of the salts and derivatives noted above may be manufactured and purified by any of several published methods . for example , the sulfatide can be prepared in high yield ( 68 %) by the reaction of the silver salt of 5 - androstene - 3β - ol - 17 - one 3 - sulfate with dipalmitoyl α - iodopropylene glycol ( abou - gharbia , m et . al ., j pharmaceutical sciences 70 : 10 , 1154 - 1157 , 1981 ). 7 - keto dhea and its isomers can be prepared by any of several published procedures ( see , for example , uspto application us 20070032462 a1 ). dhea itself can be manufactured in high yield under mild reaction conditions using the procedure outlined in cn 102212099 a , and by many other methods . dhea salicylate can be manufactured by the method described in u . s . pat . no . 5 , 736 , 537 a . dhea and its isomers , derivatives , precursors , metabolites , etc . useful in this invention can be formulated as dry powders ; as micronized or otherwise manipulated dry powders to enhance their formulation , encapsulation , compression into tablets , uptake or delivery ; as liquids , with or without flavor enhancers and stabilizers ; as semi - liquid mixtures , as for example in gel caps . dhea or its isomers , derivatives , metabolites and precursors can be administered orally as a liquid , a lozenge , a capsule or a tablet . flavor additives , stabilizers , solubilizing agents and flow enhancers and the like can be used to modify its flavor , activity , solubility and compressibility . dhea or its isomers , derivatives , metabolites and precursors may also be administered non parenterally by any number of methods including transdermally ; as a suppository ; by inhalation of respirable formulations either to the lung or nasal cavities ; by way of eye drops ; sublingually ; and by injection by any of the following routes : subcutaneous , intravenous , intraperitoneal , intracranial or intrathecal . such injections can also be formulated as depot deliveries to increase duration or effect , or to achieve another effect . dhea or its isomers , derivatives , precursors or metabolites can be formulated as described above either alone or in combination with any or more of the other components of this invention , which include bh4 , ipa , one or more nitric oxide donors , folinic acid , monoamine precursors and cofactors , ubiquinone and / or one or more tocotrienols . to prevent or adequately reduce the effects of bh4 depletion during dhea - mediated egss , bh4 can be administered , as part of the reconstitution mixture , at a dose of between , preferentially , 0 . 1 and 50 mg / kg ; more preferentially between 1 and 30 mg / kg ; and most preferentially between 5 and 25 mg / kg . bh4 can be manufactured using any one of several methods . see , for example , u . s . pat . no . 3 , 505 , 329 a ; u . s . pat . no . 8 , 178 , 670 b2 ; u . s . pat . no . 4 , 595 , 752 a ; cn101959891 a ; wo2012048451 a1 ; ca2678165 c ( crystalline forms of the dihydrochloride ); cn102443006 a ( hydrochloride ); u . s . pat . no . 4 , 649 , 197 a ( sulfate ); u . s . pat . no . 4 , 550 , 109 a ( lipoidal derivatives ); wo2013152608 a1 ( sapropterin dihydrochloride ). preparation of a sulfate of bh4 is described in ca 1250837 a1 . bh4 and its isomers , derivatives , and prodrugs useful in this invention can be formulated as dry powders ; as micronized or otherwise manipulated dry powders to enhance their formulation , encapsulation , compression into tablets , uptake or delivery ; as liquids , with or without flavor enhancers and stabilizers ; as semi - liquid mixtures , as for example in gel caps ; as respirable particles ; and the like . bh4 and its isomers , derivatives , and prodrugs can be administered orally , as a liquid , a lozenge , a capsule or a tablet . flavor additives , stabilizers , solubilizing agents and flow enhancers and the like can be used to modify its flavor , activity , solubility and compressibility . bh4 and its isomers , derivatives , and prodrugs may also be administered non parenterally by any number of methods including transdermally ; as a suppository ; by inhalation of respirable formulations either to the lung or nasal cavities ; by way of eye drops ; sublingually ; and by injection by any of the following routes : subcutaneous , intravenous , intraperitoneal , intracranial or intrathecal . bh4 and its isomers , derivatives , and prodrugs can be formulated either alone or in combination with any or all of the other components of this invention , which include dhea , ipa , one or more nitric oxide donors , folinic acid , monoamine precursors and cofactors , ubiquinone and / or one or more tocotrienols . to prevent or adequately reduce the effects of ipa depletion during dhea - mediated egss , ipa or its monophosphate ( ipamp ) can be administered , as part of the reconstitution mixture , at a dose of between , preferentially , 0 . 1 and 50 mg / kg ; more preferentially between 1 and 25 mg / kg ; and most preferentially between 2 and 10 mg / kg . ipa can also be manufactured using any one of several methods including the classical dimroth rearrangement , and by nucleophilic substitution reactions . ( see , for example , turner , m . l ., thesis , department of chemistry , atlanta university , 1980 ; robins , m . l . et . al ., biochemistry 6 : 1837 - 1848 , 1967 ; rajabi , m . et . al ., nucleic acid therapeutics 21 ( 5 ), 2011 ). ipa can also be utilized in the form of its nucleotide ( e . g ., ipa monophosphate , ipamp , or di - or tri - phoshate ). natural isoprenoid donors such as farnesol , geraniol , and geranylgeraniol can also replenish the mevalonate pathway to some degree . ipa and its isomers , derivatives , and prodrugs useful in this invention can be formulated as dry powders ; as micronized or otherwise manipulated dry powders to enhance their formulation , encapsulation , compression into tablets , uptake or delivery ; as liquids , with or without flavor enhancers and stabilizers ; as semi - liquid mixtures , as for example in gel caps ; as respirable particles ; and the like . ipa and its isomers , derivatives , and prodrugs can be administered orally , as a liquid , a lozenge , a capsule or a tablet . flavor additives , stabilizers , solubilizing agents and flow enhancers and the like can be used to modify its flavor , activity , solubility and compressibility . ipa and its isomers , derivatives , and prodrugs may also be administered non parenterally by any number of methods including transdermally ; as a suppository ; by inhalation of respirable formulations either to the lung or nasal cavities ; by way of eye drops ; sublingually ; and by injection by any of the following routes : subcutaneous , intravenous , intraperitoneal , intracranial or intrathecal . ipa and its isomers , derivatives , and prodrugs can be formulated either alone or in combination with any or all of the other components of this invention , which include dhea , bh4 , one or more nitric oxide donors , folinic acid ( or purines , pyrimidines , same ), monoamine precursors and cofactors , ubiquinone and / or one or more tocotrienols . to prevent or adequately reduce the effects of nitric oxide depletion during dhea - mediated egss , potassium nitrate ( or sodium nitrite ) can be administered , as part of the reconstitution mixture , at a dose of between , preferentially , 1 and 50 mg / kg ; more preferentially between 2 and 25 mg / kg ; and most preferentially between 3 and 15 mg / kg . potassium nitrate is available commercially in human pharmaceutical grade . other nitric oxide donors are also enveloped by our invention , including but not limited to furoxan - based dhea hybrid molecules as described in the literature ( see huang , y et . al ., steroids 2015 , may 22 , pii : s0039 - 128x ( 15 ) 00149 - x ); sodium nitrite ; nitric oxide gas ; s - nitrosothiol , diazeniumdiolate ; nonoate ; furoxan ; nitroaspirin ; and organic nitrate ( see miller , m r and megson , i l , br j pharmacol 151 ( 3 ): 305 - 321 , june , 2007 ). nitric oxide donors , derivatives , and prodrugs useful in this invention can be formulated as dry powders ; as micronized or otherwise manipulated dry powders to enhance their formulation , encapsulation , compression into tablets , uptake or delivery ; as liquids , with or without flavor enhancers and stabilizers ; as semi - liquid mixtures , as for example in gel caps ; as respirable particles ; and the like . nitric oxide donors , derivatives , and prodrugs can be administered orally , as a liquid , a lozenge , a capsule or a tablet . flavor additives , stabilizers , solubilizing agents and flow enhancers and the like can be used to modify its flavor , activity , solubility and compressibility . nitric oxide donors , derivatives , and prodrugs may also be administered non parenterally by any number of methods including transdermally ; as a suppository ; by inhalation of respirable formulations either to the lung or nasal cavities ; by way of eye drops ; sublingually ; and by injection by any of the following routes : subcutaneous , intravenous , intraperitoneal , intracranial or intrathecal . nitric oxide donors , derivatives , and prodrugs can be formulated either alone or in combination with any or all of the other components of this invention , which include dhea , bh4 , ipa , folinic acid , monoamine precursors and cofactors , ubiquinone and / or one or more tocotrienols . to prevent or adequately reduce the effects of ubiquinone depletion during dhea - mediated egss , tocotrienols , either individual isomers or as mixtures of isomers , can be administered , as part of the reconstitution mixture , at a dose of between , preferentially , 1 and 50 mg / kg ; more preferentially between 2 and 30 mg / kg ; and most preferentially between 5 and 25 mg / kg . tocotrienols can be manufactured using any one of several methods including isolation from palm and other oils ( ng , m h et . al ., lipids . 2004 october ; 39 ( 10 ): 1031 - 5 ; luidy rodriguez posada et . al ., separation and purification technology volume 57 , issue 2 , 15 october 2007 , pages 220 - 229 ), rice bran ( qureshi a a , et . al ., j agric food chem . 2000 august ; 48 ( 8 ): 3130 - 40 ), and other sources ( see n . othman , et . al ., 2010 . journal of applied sciences , 10 : 1187 - 1191 ). the palmitate , stearate and 4 - phenylbenzoate esters of d - gamma - tocotrienol can also be synthesized and purified using published procedures ( see u . s . pat . no . 5 , 670 , 668 ). tocotrienols ( α , β , γ , δ , separately or in any combination ), their derivatives , and prodrugs useful in this invention can be formulated as dry powders ; as micronized or otherwise manipulated dry powders to enhance their formulation , encapsulation , compression into tablets , uptake or delivery ; as liquids , with or without flavor enhancers and stabilizers ; as semi - liquid mixtures , as for example in gel caps ; as respirable particles ; and the like . tocotrienols ( α , β , γ , δ , separately or in any combination ), their derivatives , and prodrugs can be administered orally , as a liquid , a lozenge , a capsule or a tablet . flavor additives , stabilizers , solubilizing agents and flow enhancers and the like can be used to modify its flavor , activity , solubility and compressibility . tocotrienols ( α , β , γ , δ , separately or in any combination ), their derivatives , and prodrugs may also be administered non parenterally by any number of methods including transdermally ; as a suppository ; by inhalation of respirable formulations either to the lung or nasal cavities ; by way of eye drops ; sublingually ; and by injection by any of the following routes : subcutaneous , intravenous , intraperitoneal , intracranial or intrathecal . tocotrienols ( α , β , γ , δ , separately or in any combination ), their derivatives , and prodrugs can be formulated either alone or in combination with any or all of the other components of this invention , which include dhea , bh4 , ipa , one or more nitric oxide donors , monoamine precursors and cofactors , and ubiquinone . to prevent or adequately reduce the effects of ubiquinone depletion during dhea - mediated egss , ubiquinone can be administered , as part of the reconstitution mixture , at a dose of between , preferentially , 0 . 1 and 20 mg / kg ; more preferentially between 0 . 5 and 10 mg / kg ; and most preferentially between 1 and 5 mg / kg . ubiquinone is available in pharmaceutical grade purity or can be manufactured by any one of several methods . for example , optically pure ubiquinone can be synthesized in bulk by the process described in u . s . pat . no . 6 , 506 , 915 b1 , and u . s . pat . no . 6 , 686 , 485 and a publication mahendra , m ., et . al . ( international journal of chemical sciences and research issn print : 2249 - 0329 website : http :// www . ijcsr . co . in /). both describe a semi synthetic procedure using solanesol derived from tobacco waste as the starting material for the sterospecific synthesis of ubiquinone . additionally , large scale synthesis of ubiquinone in high yield can be performed by an sn2 ′- type nucleophilic displacement reaction between copper - catalyzed grignard reagent and allylic acetate as reported by wang , fen et . al . ( letters in organic chemistry , volume 3 , number 8 august 2006 , pp . 610 - 612 ( 3 )). ubiquinone , its derivatives , and prodrugs useful in this invention can be formulated as dry powders ; as micronized or otherwise manipulated dry powders to enhance their formulation , encapsulation , compression into tablets , uptake or delivery ; as liquids , with or without flavor enhancers and stabilizers ; as semi - liquid mixtures , as for example in gel caps ; as respirable particles ; and the like . ubiquinone , its derivatives , and prodrugs can be administered orally , as a liquid , a lozenge , a capsule or a tablet . flavor additives , stabilizers , solubilizing agents and flow enhancers and the like can be used to modify its flavor , activity , solubility and compressibility . ubiquinone , its derivatives , and prodrugs may also be administered non parenterally by any number of methods including transdermally ; as a suppository ; by inhalation of respirable formulations either to the lung or nasal cavities ; by way of eye drops ; sublingually ; and by injection by any of the following routes : subcutaneous , intravenous , intraperitoneal , intracranial or intrathecal . ubiquinone , its derivatives , and prodrugs can be formulated either alone or in combination with any or all of the other components of this invention , which include dhea , bh4 , ipa , one or more nitric oxide donors , monoamine precursors and cofactors , and one or more tocotrienols . to prevent or adequately reduce the effects of depletion of folate pathway products during dhea - mediated egss , folinic acid can be administered , as part of the reconstitution mixture , at a dose of between , preferentially , 0 . 01 and 15 mg / kg ; more preferentially between 0 . 1 and 10 mg / kg ; and most preferentially between 0 . 3 and 5 mg / kg . folinic acid can be synthesized and purified by many methods in the public domain , including that of temple , c , jr et . al . ( j med chem . 22 ( 6 ): 731 - 4 , 1979 ; sato , j k et . al ., anal biochem . 154 ( 2 ): 516 - 24 , 1986 ; u . s . pat . no . 5 , 134 , 235 a ), and by methods still under patent , for example u . s . pat . no . 8 , 633 , 202 b2 . as synthesized folinic acid exists as a mixture of optical isomers , these optical isomers can be separated by the method described in u . s . pat . no . 5 , 599 , 931 a , and by other methodologies . stabilized aqueous preparations of folinic acid , for example , for injection , can be obtained through the method described in u . s . pat . no . 6 , 613 , 767 b1 and european patent ep1640008 b1 . the sodium salt of folinic acid can be prepared according to the method described in u . s . pat . no . 6 , 160 , 116 a . folinic acid , its derivatives , salts and prodrugs useful in this invention can be formulated as dry powders ; as micronized or otherwise manipulated dry powders to enhance their formulation , encapsulation , compression into tablets , uptake or delivery ; as liquids , with or without flavor enhancers and stabilizers ; as semi - liquid mixtures , as for example in gel caps ; as respirable particles ; and the like . folinic acid , its derivatives , and prodrugs can be administered orally , as a liquid , a lozenge , a capsule or a tablet . flavor additives , stabilizers , solubilizing agents and flow enhancers and the like can be used to modify its flavor , activity , solubility and compressibility . folinic acid , its derivatives , and prodrugs may also be administered non parenterally by any number of methods including transdermally ; as a suppository ; by inhalation of respirable formulations either to the lung or nasal cavities ; by way of eye drops ; sublingually ; and by injection by any of the following routes : subcutaneous , intravenous , intraperitoneal , intracranial or intrathecal . folinic acid , its derivatives , and prodrugs can be formulated either alone or in combination with any or all of the other components of this invention , which include dhea , bh4 , ipa , one or more nitric oxide donors , monoamine precursors and cofactors , ubiquinone and / or one or more tocotrienols . to prevent or adequately reduce the effects of monoamine depletion during dhea - mediated egss , l - dopa can be administered at a dose of , preferentially , from 0 . 1 mg / kg to 25 mg / kg ; more preferentially , 0 . 5 mg / kg to 15 mg / kg ; and most preferentially from 1 mg / kg to 10 mg / kg . 5 - ht can be administered at a dose of , preferentially , 0 . 1 mg / kg to 25 mg / kg ; more preferentially , 0 . 5 mg / kg to 15 mg / kg ; and most preferentially , 1 mg / kg to 10 mg / kg . pyridoxine can be administered at a dose of , preferentially , 0 . 05 mg / kg to 5 mg / kg ; more preferentially , 0 . 09 mg / kg to 2 . 5 mg / kg ; and most preferentially , 0 . 5 mg / kg to 1 mg / kg ; same can be administered at a dose of , preferentially , 1 mg / kg to 100 mg / kg ; more preferentially , 2 mg / kg to 50 mg / kg ; and most preferentially , 5 mg / kg to 10 mg / kg . ascorbic acid can be administered at a dose of , preferentially , 1 mg / kg to 100 mg / kg ; more preferentially , 2 mg / kg to 50 mg / kg ; and most preferentially , 5 mg / kg to 25 mg / kg . pantothenic acid can be administered at a dose of , preferentially , 0 . 1 mg / kg to 100 mg / kg ; more preferentially , 0 . 5 mg / kg to 50 mg / kg ; and most preferentially , 1 mg / kg to 10 mg / kg . zinc may be administered at a dose of , preferentially , 0 . 05 mg / kg to 10 mg / kg ; more preferentially , 0 . 1 mg / kg to 5 mg / kg ; and most preferentially , 0 . 5 mg / kg to 2 . 5 mg / kg . monoamine precursors and cofactors , including l - dopa , 5ht , pyridoxine , same , ascorbate , and pantothenic acid , and zinc , can each be purchased commercially in highly purified form , or can be synthesized and purified by many methods in the public domain . highly purified l - dopa is available commercially , and can be manufactured according to standard chemical methods employing asymmetric synthesis and metal catalysts , or electroenzymatically employing a tyrosinase - immmobilized cathode under the reduction potential of dopaquinone ( see min , k et al , j . biotechnol 146 ( 1 - 2 ): 40 - 44 , 2010 ). 5 - ht is available commercially in highly purified form . it can be synthesized by many published methods ( see , for example , frangatos , g and chubb , f , can j chem 37 : 1374 - 76 , 1959 ), including a newly reported cofactor regeneration process using modified l - phenylalanine 4 - hydroxylase of chromobacterium violaceum . ( see hara , r and kino , k , amb express 3 : 70 , 2013 ). pyridoxal phosphate is available commercially in highly purified form . same is available commercially in highly purified form , of which the dihydrochloride salt is particularly useful . ascorbic acid is also available commercially in highly purified form , as are pantothenic acid and various formulations of zinc . each of these monoamine precursors or cofactors , their derivatives , salts and prodrugs useful in this invention can be formulated as dry powders ; as micronized or otherwise manipulated dry powders to enhance their formulation , encapsulation , compression into tablets , uptake or delivery ; as liquids , with or without flavor enhancers and stabilizers ; as semi - liquid mixtures , as for example in gel caps ; as respirable particles ; and the like . each of these monoamine precursors or cofactors , their derivatives , and prodrugs can be administered orally , as a liquid , a lozenge , a capsule or a tablet . flavor additives , stabilizers , solubilizing agents and flow enhancers and the like can be used to modify its flavor , activity , solubility and compressibility . each of these monoamine precursors or cofactors , their derivatives , and prodrugs may also be administered non parenterally by any number of methods including transdermally ; as a suppository ; by inhalation of respirable formulations either to the lung or nasal cavities ; by way of eye drops ; sublingually ; and by injection by any of the following routes : subcutaneous , intravenous , intraperitoneal , intracranial or intrathecal . each of these monoamine precursors or cofactors , their derivatives , and prodrugs can be formulated either alone or in combination with any or all of the other components of this invention , which include dhea , bh4 , ipa , one or more nitric oxide donors , folinic acid ( or adenine ( or hypoxanthine ) and uracil , their nucleosides or nucleotides ), ubiquinone and / or one or more tocotrienols . as used in the context of this invention , co - administration refers to temporal proximity . thus , the agents described as “ co - administered ” may be administered exactly together ; they may be delivered one or more before the other ( s ), so as to prevent the onset of negative side effects ; they may be delivered one or more after the other ( s ), for example , to cost effectively supply them only when the need becomes more pressing ; or some combination of the above . examples of binders are gum tragacanth , acacia , starch , gelatin , and biological degradable polymers such as homo - or co - polyesters of dicarboxylic acids , alkyiene glycols , polyalkyiene glycols and / or aliphatic hydroxyl carboxylic acids ; homo - or co - polyamides of dicarboxylic acids , alkylene diamines , and / or aliphatic amino carboxylic acids ; corresponding poly - ester - polyamide - co - polymers , polyanhydrides , polyorthoestens , polyphosphazene and poly - carbonates . the biological degradable polymers may be linear , branched or cross - linked . specific examples are poly - glycolic acid , poly - lactic acid , and poly - d , l - lactide / glycolide . other examples for polymers are water - soluble polymers such as polyoxalkylenes ( polyoxethylene , polyoxapropylene and mixed polymers thereof , poly - acrylamides and hydroxylalkylated polyacrylamides , poly - maleic acid and esters or - amides thereof , poly - acrylic acid and esters or - amides thereof , poly - vinylalcohol and esters or - ethers thereof , poly - vinylimidazole , poly - vinylpyrrolidon , and natural polymers like chitosan . examples for lubricants are natural or synthetic oils , fats , waxes , or fatty acid salts like magnesium stearate , sesame oil , olive oil , coconut oil , tocopherols and the like . surfactants may be ionic , anionic , amphoteric or neutral . examples for surfactants are lecithin , phospholipids , octyl sulfate , decyl sulfate , dodecyl sulfate , tetradecyl sulfate , hexadecyl sulfate and octadecyl sulfate , na oleate or na caprate , 1 - acyiaminoethane - 2 - sulfonic acids , such as 1 - octanoylaminoethane - 2 - sulfonic acid , 1 - decanoylaminoethane - 2 - sulfonic acid , 1 - dodecanoylaminoethane - 2 - sulfonic acid , 1 - tetradecanoylaminoethane - 2 - sulfonic acid , 1 - hexadecanoylaminoethane - 2 - sulfonic acid , and 1 - octadecanoylamino - ethane - 2 - sulfonic acid , and taurocholic acid and taurodeoxycholic acid , bile acids and their salts , such as cholic acid , deoxycholic acid and sodium glycocholates , sodium caprate or sodium laurate , sodium oleate , sodium lauryl sulphate , sodium cetyl sulphate , sulfated castor oil and sodium dioctylsulfosuccinate , cocamidopropylbetaine and laurylbetaine , fatty alcohols , cholesterols , glycerol mono - or - distearate , glycerol mono - or - dioleate and glycerol mono - or - dipalmitate , and polyoxyethylene stearate . examples for sweetening agents are sucrose , fructose , lactose , sodium saccharine , steviol glycosides , or aspartame . examples for flavoring agents are bacon , beef , chicken , peppermint , oil of wintergreen or fruit flavors like cherry or orange flavor . examples for coating materials are gelatin , wax , shellac , sugar or biological degradable polymers . examples for preservatives are methyl or propylparabens , sorbic acid , chlorobutanol , sodium nitrite , potassium nitrate , phenol , butylated hydroxytoluene , butylated hydroxyanisole and thimerosal . examples for thickeners are synthetic polymers , fatty acids and fatty acid salts and esters and fatty alcohols . examples for antioxidants are vitamins , such as vitamin a , vitamin c , vitamin d or vitamin e , tocopherols , tocotrienols , quercetin , curcumin , l - cysteine , l - acetyl cysteine , sesamin , sesamol , vegetable extracts or fish oils . examples for liquid carriers are water , alcohols such as ethanol , glycerol , propylene glycol , liquid polyethylene glycols , triacetin and oils . examples for solid carriers are talc , clay , micro - crystalline cellulose , silica , alumina and the like . the formulation according to the invention may also contain isotonic agents , such as sugars , buffers or sodium chloride . the hydrate form according to the invention may also be formulated as effervescent tablet or powder , which disintegrate in aqueous environment to provide a drinking solution . slow release formulations may also be prepared from the polymorph according to the invention in order to achieve a controlled release of the active agent . the formulation may be embedded for this purpose in a polymer matrix of a biological degradable polymer , a water - soluble polymer or a mixture of both , and optionally suitable surfactants . embedding can mean in this context the incorporation of microparticles in a matrix of polymers . controlled release formulations are also obtained through encapsulation of dispersed micro - particles or emulsified micro - droplets via known dispersion or emulsion coating technologies . u . s . pat . no . 5 , 567 , 696 a , 1996 , mcguire , j l , van vollenhoven , r f , and engelman , e g , treatment of systemic lupus erythematosus with dehydroepiandrosterone u . s . pat . no . 7 , 893 , 044 b2 , 2011 , nyce , jonathan w . composition and method for altering levels of or sensitivity to adenosine with analogs of dehydroepiandrosterone u . s . pat . no . 5 , 527 , 789 a , 1996 , nyce , jonathan w . method of inhibiting carcinogenesis by treatment with dehydroepiandrosterone and analogs thereof u . s . pat . no . 6 , 087 , 351 , 2000 , a nyce , jonathan w , method for reducing adenosine levels with a dehydroepiandrosterone and optionally a ubiquinone u . s . pat . no . 6 , 670 , 349 b1 , 2003 , nyce , jonathan , composition & amp ; method for altering levels of or sensitivity to adenosine with a dehydroepiandrosterone & amp ;/ or a ubiquinone u . s . pat . no . 7 , 456 , 161 b2 , 2008 , jonathan w nyce , use of dhea and dhea - sulfate for the treatment of chronic obstructive pulmonary disease u . s . pat . no . 5 , 134 , 235 a , 1992 , mueller , h r et al , process for separating folinic acid u . s . pat . no . 8 , 633 , 202 b2 , jequier , p , 2014 , crystalline levofolinic acid and process for its preparation u . s . pat . no . 5 , 599 , 931 a , ripa , g et . al ., 1997 , process for separating stereoisomers of folinic acid u . s . pat . no . 6 , 613 , 767 b1 , nijkerk , a j and vermeer , j m p , 2003 , stable aqueous folinate solution u . s . pat . no . 6 , 160 , 116 a , mueller , h r et al ., 2000 , sodium salt of ( 6s )- folinic acid wo 1996025164 a1 , 1995 use of dehydroepiandrosterone to treat depression . goodyer , ian michael , and joseph , herbert ( abstract : dehydroepiandrosterone ( dhea ) is indicated in the treatment of depression . clinical data show a statistically significant association between blood levels of dhea , abnormally low ( which can be determined by measuring the salivary dhea ), especially in the morning , and major depression , diagnosed based on recognized clinical criteria . the administration of dhea increased serum levels of dhea .) wo 1998032445 a1 , 1998 , brian berger , samuel s c yen , use of dehydroepiandrosterone to treat primary adrenal insufficiency and addison &# 39 ; s disease ( abstract : the present invention provides a method of treating an individual with primary adrenal insufficiency , comprising the step of administering an effective amount of dehydroepiandrosterone to said individual . also provided is a method of treating an individual with adrenal failure secondary to dysfunctions of the hypothalamus and / or pituitary gland , comprising the step of administering an effective amount of dehydroepiandrosterone to said individual and a method of treating an individual with adrenal insufficiency due to acquired human immunodeficiency syndrome ( aids ), comprising the step of administering an effective amount of dehydroepiandrosterone to said individual ). wo 2002043737 a1 , zenk , j l and zenk , r , 2002 , treatment of chronic fatigue syndrome and fibromyalgia syndrome ( abstract : chronic fatigue syndrome ( cfs ) and fibromyalgia syndrome ( fms ) can be treated by the administration of δ5 - androstene - 3β - ol - 7 , 17 - dione and metabolizable precursors thereof ). wo 2003002123 a3 , van der hoop , roland gerritsen , 2003 , therapeutic combinations for the treatment of hormone deficiencies ( abstract : the present invention relates to methods of treating , preventing , or reducing the risk of developing a male or female menopause disorder or symptom in a mammal by administering to the mammal a sex hormone binding globulin synthesis inhibiting agent and one or more steroids , including , for example , an androgen or an estrogen ; to combinations for treating , preventing or reducing the risk of developing a male or female menopause disorder or symptom in a mammal ; and to compositions for treating , preventing , or reducing the risk of developing a male or female menopause disorder or symptom in a mammal , where the composition comprises a sex binding globulin synthesis inhibiting agent and one or more steroids , including , for example , an androgen or an estrogen . in addition , the methods , combinations and compositions may be used in conjunction with other pharmaceutical agents aimed at improving sexual performance or impotence , increasing libido , or treating erectile dysfunction , such as viagra ®, to enhance their effectiveness ). ep 1640008 b1 , niyaji , t n p et . al ., 2011 , a stabilized aqueous ( 6s )- folinic acid preparation for injection . 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