Abstract
The degradation of rifampicin (RIF) in an acidic medium to form 3-formyl rifamycin SV, a poorly absorbed compound, is accelerated in the presence of isoniazid, contributing to the poor bioavailability of rifampicin. This manuscript presents a novel approach in which isoniazid is formulated into gastric-resistant sustained-release microspheres and RIF into microporous floating sustained-release microspheres to reduce the potential for interaction between RIF and isoniazid (INH) in an acidic environment. Hydroxypropyl methylcellulose acetate succinate and Eudragit® L100 polymers were used for the manufacture of isoniazid-loaded gastric-resistant sustained-release microspheres using an o/o solvent emulsification evaporation approach. Microporous floating sustained-release microspheres for the delivery of rifampicin in the stomach were manufactured using emulsification and a diffusion/evaporation process. The design of experiments was used to evaluate the impact of input variables on predefined responses or quality attributes of the microspheres. The percent degradation of rifampicin following 12 h dissolution testing in 0.1 M HCl pH 1.2 in the presence of isoniazid gastric-resistant sustained-release microspheres was only 4.44%. These results indicate that the degradation of rifampicin in the presence of isoniazid in acidic media can be reduced by encapsulation of both active pharmaceutical ingredients to ensure release in different segments of the gastrointestinal tract, potentially improving the bioavailability of rifampicin.
Highlights
The greatest concern regarding the use of fixed-dose combinations (FDC) for the treatment of tuberculosis (TB) is the bioavailability of rifampicin (RIF) from FDC anti-TB formulations and medicines [1,2] The decomposition of RIF in the acidic environment of the stomach varies between 8.5% and 50% over the time, corresponding to gastric residence of between 15 and 105 ± 45 min for most dosage units in humans [3,4]
The results revealed that maintaining EC at low levels and increasing the Eudragit® RLPO content resulted in an increase in % RIF released and these results were similar to previously reported data [59] in which this was attributed to the rapid ingress of dissolution medium into the microspheres due to the presence of quaternary ammonium ions in Eudragit® RLPO that facilitate dissolution of RIF present on the surface of microspheres, as well as promoting outward diffusion of RIF from the core
The results indicate that an increase in the amount of d-glucose used resulted in a reduction in the % EE of RIF that was attributed to possible disruption of the structure of the microsphere wall, and leaving spaces through which diffusion of RIF into the continuous medium could have occurred
Summary
The greatest concern regarding the use of fixed-dose combinations (FDC) for the treatment of tuberculosis (TB) is the bioavailability of rifampicin (RIF) from FDC anti-TB formulations and medicines [1,2] The decomposition of RIF in the acidic environment of the stomach varies between 8.5% and 50% over the time, corresponding to gastric residence of between 15 and 105 ± 45 min for most dosage units in humans [3,4]. Under acidic conditions in solution, RIF undergoes hydrolysis to yield 3-formyl-rifamycin SV (3-FRSV) and 1-amino 4-methylpiperazine (Figure 1). TThhee hhyyddrroollyyssiiss ooff RRIIFF uunnddeerr aacciiddiicc ccoonnddiittiioonnss iiss aacccceelleerraatteedd iinn tthhee pprreesseennccee ooff IINNHH [[55––77]]. TThhee pprroodduuccttiioonn ooff 33--FFRRSSVV,, aa ppoooorrllyy ssoolluubbllee ccoommppoouunndd tthhaatt eexxhhiibbiittss iinn vviittrroo aannttiimmiiccrroobbiiaall aaccttiivviittyy aanndd iiss iinnaaccttiivvee ininvivviov,oi,s oisneonofethoef ctohnetrcibounttirnibguftaicntgorsfatcotothres ptoootrhbeiopaovoairlabbiioliatyvaoiflaRbIiFli[t8y,9o].f TRhIeFac[8ce,9le].raTtehde dacecgerlaedraatteiodndoefgrRaIdFattoiofnoromf R3I-FFRtoSVforvmia 3r-eFvReSrsVibvleiabrienvdeirnsgibtloe tbhiendisionngitcoottihneylishoyndicroatzionnyel hdyedrirvaaztoivnee odfer3i-vFaRtiSvVe owfi3th-FIRNSHV uwnitdherINacHiduicndcoerndacitiidoincscohnads ibtieoennsphoasstubelaetnedpotostufulartthedertocofnutrrtihbeurtecotnotrthibeupteootor bthioeapvoaoilrabbiiloitayvaoiflaRbIiFliwtyhoefnRdIeFliwvehreenddfreolimveFreDdCfrfoormmFuDlaCtiofnorsm[4u,5la,7ti,1o0n]s. RpIrFesienntcheeopfrIeNseHncine aonf IFNDHC ihnasanbeFeDnCrehpaosrtbeedetnoruenpdoertregdo tgoreuantedredrgeocogmrepaotseirtidoencuomndpeorsaitciiodnicucnodnedritaiocindsicofcothnedsittioomnsacohf wthheesntocmomacpharwedhetno RcoIFmwpahreendatdomRiInFiswtehreedn vaidamthineiosrtearlerdouvtieaatlhoeneor[a4l].rTohuetereafolorneele[s4s].RTIFheisreafvoareilalbesles fRoIrFaibssaovrapitliaobnlefrfoomr aFbDsoCrpatsioconmfrpoamreFdDtoCRaIsFcaodmmpianriesdtertoedRiInF aadsempianriastteerfeodrminulaastieopna,rraetseuflotirnmguinlaptiooonr, breiosuavltainilgabiniliptyooorf bRiIoFafvraoimlabFiDlitCy foofrRmIuFlafrtoiomnsF[D3–C5f,7o]r.mulations [3,4,5,7]
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