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A Microstirring Pill Enhances Bioavailability of Orally Administered Drugs.

ABSTRACT: Majority of drugs are administered orally, yet their efficient absorption is often difficult to achieve, with a low dose fraction reaching the blood compartment. Here, a microstirring pill technology is reported with built-in mixing capability for oral drug delivery that greatly enhances bioavailability of its therapeutic payload. Embedding microscopic stirrers into a pill matrix enables faster disintegration and dissolution, leading to improved release profiles of three widely used model drugs, aspirin, levodopa, and acetaminophen, without compromising their loading. Unlike recently developed drug-carrying nanomotors, drug molecules are not associated with the microstirrers, and hence there is no limitation on the loading capacity. These embedded microstirrers are fabricated through the asymmetric coating of titanium dioxide thin film onto magnesium microparticles. In vitro tests illustrate that the embedded microstirrers lead to substantial enhancement of local fluid transport. In vivo studies using murine and porcine models demonstrate that the localized stirring capability of microstirrers leads to enhanced bioavailability of drug payloads. Such improvements are of considerable importance in clinical scenarios where fast absorption and high bioavailability of therapeutics are critical. The encouraging results obtained in porcine model suggest that the microstirring pill technology has translational potential and can be developed toward practical biomedical applications.

SUBMITTER: Mundaca-Uribe R

PROVIDER: S-EPMC8224427 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) is usually administered by injection, and its oral administration in a clinical setting has been not yet reported. Here we demonstrate the bioavailability of orally administered rhGM-CSF in healthy volunteers. The rhGM-CSF was expressed in Bombyx mori expression system (BmrhGM-CSF). METHODS AND FINDINGS: Using a single-dose, randomized, open-label, two-period crossover clinical trial design, 19 healthy volunteers were orally administered with BmrhGM-CSF (8 microg/kg) and subcutaneously injected with rhGM-CSF (3.75 microg/kg) respectively. Serum samples were drawn at 0.0h, 0.5h ,0.75h,1.0h,1.5h,2.0h ,3.0h,4.0h,5.0h,6.0h,8.0h,10.0h and 12.0h after administrations. The hGM-CSF serum concentrations were determined by ELISA. The AUC was calculated using the trapezoid method. The relative bioavailability of BmrhGM-CSF was determined according to the AUC ratio of both orally administered and subcutaneously injected rhGM-CSF. Three volunteers were randomly selected from 15 orally administrated subjects with ELISA detectable values. Their serum samples at the 0.0h, 1.0h, 2.0h, 3.0h and 4.0h after the administrations were analyzed by Q-Trap MS/MS TOF. The different peaks were revealed by the spectrogram profile comparison of the 1.0h, 2.0h, 3.0h and 4.0h samples with that of the 0.0h sample, and further analyzed using both Enhanced Product Ion (EPI) scanning and Peptide Mass Fingerprinting Analysis. The rhGM-CSF was detected in the serum samples from 15 of 19 volunteers administrated with BmrhGM-CSF. Its bioavailability was observed at an average of 1.0%, with the highest of 3.1%. The rhGM-CSF peptide sequences in the serum samples were detected by MS analysis, and their sizes ranging from 2,039 to 7,336 Da. CONCLUSIONS: The results demonstrated that the oral administered BmrhGM-CSF was absorbed into the blood. This study provides an approach for an oral administration of rhGM-CSF protein in clinical settings. TRIAL REGISTRATION: www.chictr.orgChiCTR-TRC-00000107.

Project description:Polymeric coatings are a promising option for the development of delivery systems for orally administered drugs. However, the gastrointestinal conditions to which they are subjected, which include low pH and solubility as well as peristaltic movements, can limit their applications. In this work, different formulations of polymeric coatings were produced using pH-sensitive materials consisting of copolymers of methyl acrylate, methyl methacrylate, and methacrylic acid. The polymers were synthesized by the emulsion polymerization technique, obtaining small average particle sizes (56-190 nm), molecular weights between 200,000 and 400,000 g/mol, and a glass transition temperature above 35 °C, which are suitable for film formation at room temperature. Thus, they were assessed as coatings for hydroxypropyl methylcellulose capsules (HPMC) using the immersion method, showing adequate capacity to protect the capsule at gastric pH (pH 1.2) and dissolve at the simulated intestinal pH (pH= 7.2). In particular, the higher the content of the acidic monomer, the higher the release time of the test molecule contained in the acrylic terpolymer-coated HPMC capsules proposed, which was a curcuminoid derivative due to their bright color and potential medical benefits. In addition, a minimum number of immersions was required for coating the HPMC capsules at high acidic concentrations, which further facilitates the delayed release needed for colonic treatment. However, too high proportions of methacrylic acid may result in cytotoxicity issues. Consequently, a biocompatible formulation containing a proportion of methyl acrylate, methyl methacrylate, and methacrylic acid of 7:3:3 is proposed as the most adequate for colonic release. Thus, by chemically modulating the molar percentages of the acrylic monomers, it was possible to obtain tailored acrylic terpolymer coatings with different characteristics and desired properties in order to modulate the release kinetics of an active substance in a colonic environment.

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A Microstirring Pill Enhances Bioavailability of Orally Administered Drugs.

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