Abstract
Amorphous solid dispersions (ASDs) are of great interest due to their ability to enhance the delivery of poorly soluble drugs. Recent studies have shown that, in addition to acting as a crystallization inhibitor, the polymer in an ASD plays a role in controlling the rate of drug release, notably in congruently releasing formulations, where both the drug and polymer have similar normalized release rates. The aim of this study was to compare the solid-state stability and release performance of ASDs when formulated with neutral and enteric polymers. One neutral (polyvinylpyrrolidone-vinyl acetate copolymer, PVPVA) and four enteric polymers (hypromellose acetate succinate; hypromellose phthalate; cellulose acetate phthalate, CAP; methacrylic acid-methyl methacrylate copolymer, Eudragit L 100) were used to formulate binary ASDs with lumefantrine, a hydrophobic and weakly basic antimalarial drug. The normalized drug and polymer release rates of lumefantrine-PVPVA ASDs up to 35% drug loading (DL) were similar and rapid. No drug release from PVPVA systems was detected when the DL was increased to 40%. In contrast, ASDs formulated with enteric polymers showed a DL-dependent decrease in the release rates of both the drug and polymer, whereby release was slower than for PVPVA ASDs for DLs < 40% DL. Drug release from CAP and Eudragit L 100 systems was the slowest and drug amorphous solubility was not achieved even at 5% DL. Although lumefantrine-PVPVA ASDs showed fast release, they also showed rapid drug crystallization under accelerated stability conditions, while the ASDs with enteric polymers showed much greater resistance to crystallization. This study highlights the importance of polymer selection in the formulation of ASDs, where a balance between physical stability and dissolution release must be achieved.
Highlights
Drug solubility is important for orally administered dosage forms to ensure that the desired plasma concentration to achieve therapeutic efficacy is reached
Studies have shown that polymer-controlled dissolution in binary Amorphous solid dispersions (ASDs) leads to the congruent release of the drug and polymer; that is, the two components release simultaneously at the same normalized rate
Article because the neat polymer dissolution rate is typically much faster than that of a lipophilic amorphous drug, the drug release rate from ASDs is enhanced in the polymer-controlled regime
Summary
Drug solubility is important for orally administered dosage forms to ensure that the desired plasma concentration to achieve therapeutic efficacy is reached. One example of a poorly soluble drug is lumefantrine, which has a reported crystalline solubility of 2.6 ng/mL in fasted state simulated intestinal fluid.[2] Lumefantrine is an antimalarial drug used in combination with artemether for the treatment of multidrug resistant strains of Plasmodium falciparum malaria. Artemether serves as the rapid-acting drug to reduce the parasite biomass, while lumefantrine acts over a longer period to eliminate the residual parasites, thereby minimizing the risk of recrudescence.[3] Approved by the United States Food and Drug Administration in 2008 and marketed as a fixed-dose oral combination of lumefantrine (120 mg) and artemether (20 mg) under the brand name Coartem, the treatment regimen consists of a three-day treatment schedule with a total of six doses. The treatment regime with Coartem involves a rather high pill burden, which could potentially contribute to patient nonadherence, exacerbating the prevalence of drugresistant malaria
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