Abstract
Hydrochlorothiazide (HCT), a Biopharmaceutical Classification System (BCS) class IV drug, is characterized by low solubility and permeability, that negatively affect its oral bioavailability, reducing its therapeutic efficacy. The combined use of cyclodextrins (CDs) and nanoclays (NCs) recently proved to be a successful strategy in developing delivery systems able to merge the potential benefits of both carriers. In this work, several binary systems of CDs or NCs with the drug were obtained, using different drug:carrier ratios and preparation techniques, and characterized in solution and in solid state, to properly select the most effective system and preparation method. Then, the best CD (RAMEB) and NC (sepiolite), at the best drug:carrier ratio, was selected for preparation of the ternary system by co-evaporation and emerged as the most effective preparation method. The combined presence of RAMEB and sepiolite gave rise to a synergistic improvement of drug dissolution properties, with a two-fold increase in the amount of drug dissolved as compared with the corresponding HCT-RAMEB system, resulting in an approximately 12-fold increase in drug solubility as compared with the drug alone. The ternary system that was co-evaporated was then selected for a tablet formulation. The obtained tablets were fully characterized for technological properties and clearly revealed a better drug dissolution performance than the commercial reference tablet (Esidrex®).
Highlights
Hydrochlorothiazide (HCT) is a thiazide diuretic drug widely used in the treatment of heart failure, hypertension, hypovolemic shock, or edema [1]
CoAncnluesxihoanusstive study of the interactions between HCT and several kinds of cyclodextrins, in coAmnbienxahtiaounswtivitehsdtuiffdeyreonft tphreepinarteartiaocntiomnesthboedtws efoernbHinCaTryasnydstesmevserreaslukltineddsinotfhceysceloledcetixotnrinosf,thine cCoOmEbpinraotdiounctwwiitthh dRiAffMerEenBtapsrtehpeamraotisotnapmperothpordiastefotor biminparroyvseydsrtuemg sdirsessoulultteidoninprtohpeesretileesc,tiaosnaorfestuhlet CofOthEepbreosdt ucoctmwpliethxinRgA-sMolEuBbialiszitnhgeambiolistty aopfpsurocphrCiaDteatnoditmheprcoovmepdlertuegddruisgsoamluotiropnhipzraotipoenrtaicehs,ieavseda rbeysucolt-eovf atpheorbaetsiotncoinmiptslepxriensge-nsocelu. bSiolilzidin-gstaatbeilsittuydoifessuocfhHCCDT ainndmtihxetucroems wpliethtetdhrreuegtaympeosrpohf iNzaCtsioant achieved by co-evaporation in its presence
Solid-state studies of HCT in mixtures with three types of NCs at different w/w ratios led to the choice of SV at the 1:4 w/w ratio as the best for establishing effective interactions with the drug
Summary
Hydrochlorothiazide (HCT) is a thiazide diuretic drug widely used in the treatment of heart failure, hypertension, hypovolemic shock, or edema [1]. HCT is a class IV drug, according to the Biopharmaceutical Classification System (BCS), characterized by low aqueous solubility and low permeability [2]. Due to these factors, this drug is poorly absorbed in the gastrointestinal tract, resulting in a variable and low bioavailability after oral administration [3]. Cyclodextrins (CDs) are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity used as complexing agents to increase aqueous solubility of poorly soluble drugs and to increase their bioavailability and stability. ΒCD has relatively low solubility and often cannot be used at concentrations suitable for pharmaceutical applications. For these reasons several modified βCDs have been prepared, and its hydroxypropyl, methyl, and sulfobutylether derivatives have been commercially used as new pharmaceutical excipients
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