Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug–bile interaction

Takemura, Shigeo; Kondo, Hiromu; Watanabe, Susumu; Sako, Kazuhiro; Ogawara, Ken Ichi; Higaki, Kazutaka

doi:10.1002/jps.23484

Cited by 5 publications

(7 citation statements)

References 16 publications

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“…Surprisingly, in our study, while E100 was soluble in the formulation, it was not soluble at the levels examined in simulated fasted intestinal fluid (whereas previous studies suggest solubility in aqueous buffers). Takemura et al have previously reported an interaction of E100 with taurocholate bile salt, and this may explain its observed precipitation in the micellar solution employed here . Takemura et al attributed this detrimental interaction to an electrostatic and/or hydrophobic contact between the anionic amphiphile (bile salt) and the hydrophobic backbone of the cationionic copolymer.…”

Section: Discussionmentioning

confidence: 67%

“…Takemura et al have previously reported an interaction of E100 with taurocholate bile salt, and this may explain its observed precipitation in the micellar solution employed here. 67 Takemura et al attributed this detrimental interaction to an electrostatic and/or hydrophobic contact between the anionic amphiphile (bile salt) and the hydrophobic backbone of the cationionic copolymer.…”

Section: ■ Discussionmentioning

confidence: 99%

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Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

et al. 2018

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The ability of lipid-based formulations (LBFs) to increase the solubilization, and prolong the supersaturation, of poorly water-soluble drugs (PWSDs) in the gastrointestinal (GI) fluids has generated significant interest in the past decade. One mechanism to enhance the utility of LBFs is to prolong supersaturation via the addition of polymers that inhibit drug precipitation (polymeric precipitation inhibitors or PPIs) to the formulation. In this work, we have evaluated the performance of a range of PPIs and have identified PPIs that are sufficiently soluble in LBF to allow the construction of single phase formulations. An in vitro model was first employed to assess drug (fenofibrate) solubilization and supersaturation on LBF dispersion and digestion. An in vitro-in situ model was subsequently employed to simultaneously evaluate the impact of PPI enhanced drug supersaturation on drug absorption in rats. The stabilizing effect of the polymers was polymer specific and most pronounced at higher drug loads. Polymers that were soluble in LBF allowed simple processing as single phase formulations, while formulations containing more hydrophilic polymers required polymer suspension in the formulation. The lipid-soluble polymers Eudragit (EU) RL100 and poly(propylene glycol) bis(2-aminopropyl ether) (PPGAE) and the water-soluble polymer hydroxypropylmethyl cellulose (HPMC) E4M were identified as the most effective PPIs in delaying fenofibrate precipitation in vitro. An in vitro model of lipid digestion was subsequently coupled directly to an in situ single pass intestinal perfusion assay to evaluate the influence of PPIs on fenofibrate absorption from LBFs in vivo. This coupled model allowed for real-time evaluation of the impact of supersaturation stabilization on absorptive drug flux and provided better discrimination between the different PPIs and formulations. In the presence of the in situ absorption sink, increased fenofibrate supersaturation resulted in increased drug exposure, and a good correlation was found between the degree of in vitro supersaturation and in vivo drug exposure. An improved in vitro-in vivo correlation was apparent when comparing the same formulation under different supersaturation conditions. These observations directly exemplify the potential utility of PPIs in promoting drug absorption from LBF, via stabilization of supersaturation, and further confirm that relatively brief periods of supersaturation may be sufficient to promote drug absorption, at least for highly permeable drugs such as fenofibrate.

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Section: Discussionmentioning

confidence: 67%

Section: ■ Discussionmentioning

confidence: 99%

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

et al. 2018

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“…Although sodium alginate and HPMC had no effect, AAM copolymer E prevented this complex formation (Figure ). AAM copolymer E increased absorption of the drug by about 2 times after oral dosing to rats, probably due to interaction of the polymer with bile acids as opposed to the drug . This formulation contained a 3-fold greater amount of polymer than the drug, which might result in large-sized capsules or tablets.…”

Section: Amount-controlled Ddsmentioning

confidence: 99%

“…AAM copolymer E increased absorption of the drug by about 2 times after oral dosing to rats, probably due to interaction of the polymer with bile acids as opposed to the drug. 101 This formulation contained a 3-fold greater amount of polymer than the drug, which might result in large-sized capsules or tablets. Spray-driers and fluid bed granulators are commonly utilized to manufacture the formulation.…”

Section: Prevention Of Interacting With Gastrointestinal Contentsmentioning

confidence: 99%

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Oral Drug Delivery Systems Applied to Launched Products: Value for the Patients and Industrial Considerations

Yoshida,

Kojima

2023

Mol. Pharmaceutics

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Drug delivery systems (DDS) control the amount, rate, and site of administration of drug substances in the body as well as their release and ADME (absorption, distribution, metabolism, excretion). Among the various types of DDS, amount-controlled DDS for solubilization and absorption increase the bioavailability. Time-and amount-controlled DDS are controlled release formulations classified as (1) membrane-type, (2) matrix-type, (3) osmotic-type, and (4) ion-exchange type. Timed-release formulations also control the time and amount of release and the absorption of drugs. Site-and amount-controlled DDS are characterized by colonic delivery and intestinal lymphtargeting to improve release and ADME of drug substances. Finally, site-, time-, and amount-controlled DDS are gastroretentive formulations and local delivery in the oral cavity to improve site retention, release, and ADME of drugs. DDS can enhance efficacy, reduce adverse effects, and optimize the dosing frequency of various drug products to increase patient value. This review focuses on patient value and industrial considerations of launched oral DDS. We provide a technological overview of candidate and marketed DDS, as well as the pros/cons of the technologies for industrialization with consideration to excipients, manufacturing, and storage stability. Moreover, to demonstrate the usefulness of the technology and support the selection and development of the best technologies for patients, we also describe patient value from clinical studies and analyses, particularly with regard to increased new medical options, higher efficacy, reduced adverse effects, reduced number of doses and clinic visits, easier administration, higher quality of life, greater adherence, and satisfaction.

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Absorption improvement of sepantronium bromide (YM155) by aminoalkyl methacrylate copolymers in in situ intestinal tracts of mice

Ishii

Kobayashi

Maeda

et al. 2015

Journal of Drug Delivery Science and Technology

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Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug–bile interaction

Cited by 5 publications

References 16 publications

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

Polymeric Precipitation Inhibitors Promote Fenofibrate Supersaturation and Enhance Drug Absorption from a Type IV Lipid-Based Formulation

Oral Drug Delivery Systems Applied to Launched Products: Value for the Patients and Industrial Considerations

Absorption improvement of sepantronium bromide (YM155) by aminoalkyl methacrylate copolymers in in situ intestinal tracts of mice

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