Patent Application: US-89877104-A

Abstract:
transporters are membrane proteins that translocate solutes across biological membranes . active agents such as drugs , prodrugs , nutrients , nutraceuticals , and other bioactive substances are substrates for transporters . some transporters require sodium to be co - transported with solute , in order to transport solute . this invention relates to a pharmaceutical formulation approach to enhance uptake of active agent by increasing the uptake of active agent by a sodium - dependent transporter , where sodium is fabricated with or co - administered with active agent . one example is the formulation of a dosage form containing the prodrug acyclovir valychenodeoxycholate , which targets the human apical sodium - dependent bile acid transporter , and sodium chloride to enhance active agent uptake from the gastrointestinal tract .

Description:
this formulation approach relies on sodium - dependent transporter - mediated uptake , but is not limited to active agents with only one therapeutic category . enhanced oral absorption is the primary area of potential application . the use of a material with a relatively high sodium composition on a weight basis , especially sodium chloride , is preferred . preferably , co - administration of sodium will be achieved by formulating active agent with sodium in a dosage form , where at least 0 . 5 milliequivalent of sodium is present . the following materials were use . acyclovir valychenodeoxycholate was synthesized in dr . polli &# 39 ; s laboratory using previously described methods ( 10 ). captopril deoxycholate was similarly synthesized in dr . polli &# 39 ; s laboratory . biotin , zidovudine , ribavirin , alanine , and ascorbic acid were obtained from sigma ( st . louis , mo .). sodium chloride and sodium citrate tribasic dihydrate were obtained from sigma ( st . louis , mo .). microcrystalline cellulose ( avicel ph101 ) and croscarmellose sodium ( ac - di - sol ) were obtained from fmc biopolymer ( newark , del .). magnesium stearate , sodium phosphate monobasic granular , sodium citrate tribasic dihydrate granular , and sodium starch glycolate were obtained from spectrum ( gardina , calif .). sodium phosphate dibasic anhydrous was obtained from em industries ( gibbstown , n . j .). silicified microcrystalline cellulose ( prosolv smcc90 ) was obtained from mendell ( patterson , n . j .). crospovidone ( polyplasdone xl - 10 ) was obtained from isp technologies inc . ( wayne , n . j .). lactose anhydrous was obtained from quest international ( hoffman estates , ill .). corn starch was obtained from roquette america inc . ( keokuk , iowa ). dicalcium phosphate anhydrous was obtained from rhone - poulenc ( cranbury , n . j .). carboxymethylcellulose sodium was obtained from sigma ( st . louis , mo .). for a number of active agents , tablets containing an active agent that is a substrate for a sodium - dependent transporter and containing sodium were fabricated . for each active agent , tablets were characterized in terms of their hardness and in vitro dosage form release properties , specifically in vitro disintegration and in vitro dissolution of sodium . using a compendial dissolution test , each dosage form delivered sodium to the dissolution medium , from where active agent is taken up by one ( or more ) sodium - dependent transporters . tablets were formulation to containing sodium and active agent that was a substrate for a sodium - dependent transporter . formulations a - k were manufactured . capsules , powders , solutions , suspensions , and other dosage forms are also possible ( 60 ). co - administration of a formulation of active agent and a formulation of sodium is also possible . each formulation a - k contains sodium ( i . e . a material containing sodium , typically a sodium salt ). sodium - possessing formulation components were : sodium chloride , croscarmellose sodium , sodium phosphate dibasic anhydrous , sodium citrate tribasic dihydrate , sodium phosphate monobasic granular , sodium citrate tribasic dihydrate granular , sodium starch glycolate , and carboxymethylcellulose sodium . many other sodium - possessing excipients are suitable as formulation components to provide sodium , and can also provide formulation benefit as fillers , binder , buffers , disintegrants , and other roles known in the art ( 61 - 63 ). while the current examples indicate the fabrication of a formulation that includes a sodium - possessing substance and an active agent , the describe approach can also be applied when the sodium - possessing substance and the active agent are not formulated as one dosage form , but are co - administered . however , the inclusion of sodium in a dosage form of active agent is preferable , as this approach is generally convenient . each formulation also contained an active agent that is a substrate for a transporter that co - transports sodium ion . in these examples , active agents were : acyclovir valychenodeoxycholate , captopril deoxycholate , biotin , zidovudine , ribaviran , alanine , and ascorbic acid . sodium salts of the active also can provide sodium . formulations and other administration regimens can also include more than one active agent . in the examples below , most formulations also employed materials that were neither the active agent nor sodium - possessing ( 60 ). examples include microcrystalline cellulose , magnesium stearate , silicified microcrystalline cellulose , crospovidone , lactose anhydrous , corm starch , and dicalcium phosphate anhydrous . such materials are well - known to facilitate dosage form fabrication and / or dosage for performance . for each formulation , six tablets were subjected to tablet hardness testing using a key hardness tester [ model ht - 300 ] ( key international , inc ., elizabeth , n . j .). values were measure in units of kilopond ( kp ) and converted to units of newton ( n ). for each formulation , tablet disintegration testing and tablet dissolution testing were performed to assess the ability of the tablet to provide sodium ion into the surrounding medium . six tablets were evaluated in the disintegration test . either six or twelve tablets were evaluated in the dissolution test . the disintegration apparatus conformed to usp compendial specifications . the disintegration apparatus components [ model vanderkamp ] were manufactured by van kel industries ( edison , n . j . ): the basket - rack assembly , motor , water heater , and water bath . disintegration was performed at 30 cycles / min using 900 ml water at 37 ° c . in a 1 l flat - bottom flask . the dissolution apparatus conformed to usp compendial specifications . the apparatus was manufactured [ model vk 700 ] by van kel industries ( edison , n . j . ), and also employed a water heater [ model vk 750d ] ( van kel industries , edison , n . j .). dissolution was performed with paddle using either 900 ml water at 37 ° c . or 900 ml water that had been adjusted to ph 1 . 5 at 37 ° c . water was employed in evaluating formulations a , b , c , g , h , i , j , and k . water adjusted to ph 1 . 5 was employed in evaluating formulations d , e , and f . a single sample was taken from each vessel at either 5 , 10 , or 30 min . sodium was quantified using a jenway flame photometer [ model pfp7 ] ( jenway , princeton , n . j .). the standard curve was linear ( r 2 = 0 . 997 ); standards were fitted with acceptable accuracy (& lt ; 2 % error ). results were analyzed by student &# 39 ; s t - test or by anova with post hoc analysis , using spss version 10 ( spss , chicago , ill .). a p - value less than 0 . 05 was considered significant . sem &# 39 ; s of ratios were calculated by the delta method . formulations a - k each resulted in tablets that were white , round , and flat - faced . other tablet tooling can be employed to provide other tablet shapes . other excipients or formulations processes ( e . g . coating ) can be used to yield other tablet appearance . for each formulation , tablet hardness , disintegration , and dissolution attributes are listed below . disintegration and sodium ion dissolution data reflect availability of sodium ion from the formulation . tablets were fabricated from a powder mixture of acyclovir valychenodeoxycholate ( 100 mg / tablet ), sodium chloride ( 250 mg / tablet ), and microcrystalline cellulose ( 150 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 500 mg of powder mixture was compressed on a carver laboratory press [ model 4687 ] ( fred s . carver inc ., menomee falls , wis .) using tablet tooling . the compact was compressed to 500 psi for 60 sec . tablet hardness of formulation a tablet tablet hardness ( n ) 1 28 . 4 2 31 . 4 3 32 . 4 4 28 . 4 5 30 . 4 6 32 . 4 mean (± se ) 30 . 6 (± 0 . 8 ) tablets were fabricated from a powder mixture of acyclovir valychenodeoxycholate ( 200 mg / tablet ) and sodium chloride ( 300 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 500 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation b tablet tablet hardness ( n ) 1 39 . 2 2 36 . 3 3 40 . 2 4 41 . 2 5 37 . 3 6 38 . 2 mean (± se ) 38 . 7 (± 0 . 7 ) tablets were fabricated from a powder mixture of acyclovir valychenodeoxycholate ( 200 mg / tablet ), sodium chloride ( 300 mg / tablet ), croscamellose sodium ( 20 mg / tablet ), and magnesium stearate ( 4 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 524 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation c tablet tablet hardness ( n ) 1 33 . 3 2 33 . 3 3 31 . 4 4 37 . 3 5 34 . 3 6 35 . 3 mean (± se ) 30 . 6 (± 0 . 7 ) tablets were fabricated from a powder mixture of acyclovir valychenodeoxycholate ( 200 mg / tablet ) and sodium phosphate dibasic anhydrous ( 200 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 400 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation d tablet tablet hardness ( n ) 1 34 . 3 2 33 . 3 3 33 . 3 4 35 . 3 5 34 . 3 6 36 . 3 mean (± se ) 34 . 5 (± 0 . 4 ) tablets were fabricated from a powder mixture of acyclovir valychenodeoxycholate ( 200 mg / tablet ), sodium phosphate dibasic anhydrous ( 200 mg / tablet ), silicified microcrystalline cellulose ( 100 mg / tablet ), crospovidone ( 20 mg / tablet ), and magnesium stearate ( 4 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 524 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation e tablet tablet hardness ( n ) 1 37 . 3 2 65 . 7 3 41 . 2 4 46 . 1 5 47 . 1 6 48 . 1 mean (± se ) 47 . 6 (± 4 . 6 ) tablets were fabricated from a powder mixture of captopril deoxycholate ( 25 mg / tablet ), sodium citrate tribasic dihydrate ( 250 mg / tablet ), microcrystalline cellulose ( 150 mg / tablet ), lactose anhydrous ( 50 mg / tablet ), croscarmellose sodium ( 30 mg / tablet ), and magnesium stearate ( 3 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 508 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation f tablet tablet hardness ( n ) 1 56 . 9 2 55 . 9 3 50 . 0 4 57 . 9 5 60 . 8 6 53 . 9 mean (± se ) 55 . 9 (± 1 . 4 ) tablets were fabricated from a powder mixture of biotin ( 30 microgram / tablet ), sodium phosphate monobasic granular ( 100 mg / tablet ), microcrystalline cellulose ( 200 mg / tablet ), and corn starch ( 20 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 320 . 030 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation g tablet tablet hardness ( n ) 1 60 . 8 2 63 . 7 3 65 . 7 4 53 . 0 5 57 . 9 6 60 . 8 mean (± se ) 60 . 3 (± 1 . 7 ) tablets were fabricated from a powder mixture of zidovudine ( 100 mg / tablet ), sodium citrate tribasic dihydrate granular ( 100 mg / tablet ), silicified microcrystalline cellulose ( 200 mg / tablet ), lactose anhydrous ( 50 mg / tablet ), and sodium starch glycolate ( 25 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 475 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation h tablet tablet hardness ( n ) 1 46 . 1 2 41 . 2 3 40 . 2 4 47 . 1 5 52 . 0 6 50 . 0 mean (± se ) 46 . 1 (± 1 . 7 ) tablets were fabricated from a powder mixture of ribavirin ( 200 mg / tablet ), sodium chloride ( 150 mg / tablet ), microcrystalline cellulose ( 200 mg / tablet ), lactose anhydrous ( 25 mg / tablet ), and magnesium stearate ( 3 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 478 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation i tablet tablet hardness ( n ) 1 41 . 2 2 46 . 1 3 47 . 1 4 38 . 2 5 40 . 2 6 38 . 2 mean (± se ) 41 . 8 (± 1 . 4 ) tablets were fabricated from a powder mixture of alanine ( 100 mg / tablet ), sodium chloride ( 200 mg / tablet ), sodium phosphate monobasic granular ( 50 mg / tablet ), silicified microcrystalline cellulose ( 100 mg / tablet ), and croscarmellose sodium ( 40 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 490 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation j tablet tablet hardness ( n ) 1 41 . 2 2 50 . 0 3 37 . 3 4 38 . 2 5 44 . 1 6 50 . 0 mean (± se ) 43 . 5 (± 2 . 1 ) tablets were fabricated from a powder mixture of ascorbic acid ( 100 mg / tablet ), sodium chloride ( 150 mg / tablet ), dicarcium phosphate anhydrous ( 25 mg / tablet ), silicified microcrystalline cellulose ( 100 mg / tablet ), carboxymethylcellulose sodium ( 25 mg / tablet ), and croscarmellose sodium ( 25 mg / tablet ). individual components were weighed out for 20 tablets and combined in a mortar to yield a uniform mixture . 425 mg of powder mixture was compressed on a carver laboratory press . the compact was compressed to 1000 psi for 60 sec . tablet hardness of formulation k tablet tablet hardness ( n ) 1 44 . 1 2 41 . 2 3 46 . 1 4 50 . 0 5 40 . 2 6 42 . 2 mean (± se ) 44 . 0 (± 1 . 4 ) the above formulations serve as examples . this approach provides for the delivery of sodium ion along with the delivery of an active agent that targets for a sodium - dependent transporter , in order to enhance uptake of the active agent . targets indicates that the active agent is a substrate for a sodium - dependent transporter . in formulation a , the solute is acyclovir valylchenodeoxycholate , a prodrug of acyclovir and which targets the bass family , including the human apical sodium - dependent bile acid transporter ( hasbt ). a tablet was designed and manufactured to include both the prodrug and sodium chloride , as source of sodium ion . other dosage forms ( e . g . capsules , waffer ) and other regimens ( e . g . co - administration of two dosage forms , one containing the active agent and the other providing sodium ) are possible . other sources of sodium ( e . g . sodium citrate , sodium phosphate ) can be included in addition to sodium chloride and / or in place of sodium chloride . sodium species are not typically designed into tablet and capsule formulations . the tablet was designed to release sodium in an immediate release fashion . other release profiles ( e . g . sustained release , delayed release ) are also possible . disintegration and dissolution are common in vitro tools to predict in vivo performance . disintegration and dissolution are compendial tests . disintegration and dissolution data indicate the availability of sodium ion from the dosage form into the medium from which prodrug is taken up by the transporter . cell uptake studies indicate sodium to enhance hasbt uptake of prodrug . this prodrug approach itself has been shown in rats to enhance acyclovir oral bioavailability . this formulation approach is applicable to other sodium - dependent transporters in the gastrointestinal tract and throughout the body . hence , in addition to improved oral absorption from the gut , this approach can improve the uptake of active agents into other tissues and organs ( e . g . uptake to brain ). all references cited herein are incorporated by reference in their entirety . 1 . busch w . saier m h jr . the transporter classification ( tc ) system , 2002 . critical reviews in biochemistry & amp ; molecular biology . 37 ( 5 ): 287 - 337 , 2002 . 2 . saier m h jr . a functional - phylogenetic classification system for transmembrane solute transporters . microbiology & amp ; molecular biology 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( 2004 ): summary workshop report : biopharmaceutics classification system — implementation challenges and extension opportunities . journal of pharmaceutical sciences 93 : 1375 - 1381 . 63 . the fda has recently made available to the public the inactive ingredients database , which lists inactive ingredients in fda - approved drug products . the inactive ingredients database can be accessed at http :// www . accessdata . fda . gov / scripts / cder / iig / index . cfm . this list is searchable by ingredient name . each database cites the maximum amount of inactive ingredient for each route / dosage form containing the inactive ingredient . although the description above contains many specificities , these should not be construed as limiting the scope of the invention , but as merely as providing illustrations of some of the preferred embodiments of this invention .