ReportDrug Delivery

A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment

See allHide authors and affiliations

Science Translational Medicine  13 Mar 2019:
Vol. 11, Issue 483, eaau6267
DOI: 10.1126/scitranslmed.aau6267
  • Fig. 1 Design and in vivo evaluation of a large-dose GRS for drug delivery.

    (A) (i-ii) An NG tube is first placed as a conduit for the large-dose GRS to be non-surgically administered, and then the NG tube is removed from the patient. (iii-iv) The GRS resides in the gastric cavity while releasing drugs. (v-vi) An NG tube is again placed in the patient for deployment of a retrieval device to attach and remove the GRS from the gastric cavity. Black arrows indicate direction of movement of the NG tube and retrieval device, and red arrows indicate drug release. (B) The GRS consists of a series of drug pills on a coiled superelastic nitinol wire; the ends are protected with a retainer and tubing. (C) Representative radiographs of the GRS immediately after deployment and on day 28 in a swine model. Dashed circles indicate GRS location. (D) The retrieval device consists of a Hall effect sensor and a magnet that can detect and attach to the magnets on either end of the GRS. Representative stepwise radiographs of the retrieval process executed in a swine model are shown below. Dashed circles indicate coupling of retrieval device with GRS. The components of both ends of the GRS [glue, a retainer, and a poly(Ɛ-caprolactone) (PCL) plug] are also shown.

  • Fig. 2 Fabrication and in vitro release of TB antibiotics from individual drug pills.

    (A) Coated drug pills are made by mixing drug with silicones and extracting individual pills from the homogeneous matrix using a biopsy punch before spray-coating pills in a pan coater. A schematic visualization and a cross-sectional image of the Eudragit RS 100–coated doxycycline hyclate pill are shown. (B) In vitro release of doxycycline hyclate from a drug pill in SGF with formulations including different concentrations of PEG and Eudragit RS 100 coatings. (C) In vitro release of isoniazid from a drug pill in water. (D) In vitro release of ethambutol from a drug pill in SGF. (E) In vitro release of pyrazinamide from a drug pill in SGF. (F) In vitro release of moxifloxacin from a drug pill in SGF. (G) In vitro release of rifampicin in water from devices with 2 g of drug and 0% PEG. Inset: Image of the rifampicin-loaded device. Error bars represent SD for n = 3 samples in each group.

  • Fig. 3 In vivo release of doxycycline hyclate from the GRS in a swine model.

    (A) Representative photograph of a GRS after assembly of drug pills along a nitinol wire before deployment in vivo. (B) Representative photo of a retrieved GRS after 28 days in vivo in a swine model. (C) Left: Concentration-time profiles of doxycycline hyclate in serum after administering a single dose of 100 mg (n = 3). Right: Concentration-time profiles of doxycycline hyclate in serum after administering the GRS, which had 10 g of drug across four formulations (n = 3; fig. S5). (D) Area under the curve (AUC) and the duration of drug release for a single dose compared to the formulations of the GRS administered in vivo, with the mean value and SD reported for n = 3 samples in each group.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/11/483/eaau6267/DC1

    Materials and Methods

    Fig. S1. Physical parameters of the GRS as the drug weight increases.

    Fig. S2. Serial radiographs of the GRS over 1 month in a swine model.

    Fig. S3. Effect of the GRS on the weight and stomach tissue of swine.

    Fig. S4. Hall effect sensor acid stability and retrieval using an in vitro stomach model.

    Fig. S5. In vivo formulations and their corresponding 4-week in vitro drug release profiles of doxycycline hyclate–silicone pills of the 10 g GRS.

    Fig. S6. In vivo release of rifampicin from the GRS in a swine model.

    Fig. S7. Field questionnaire results at TB clinics in New Delhi, India.

    Fig. S8. Field questionnaire results on NG tube deployment at TB clinics in New Delhi, India.

    Table S1. Demographics of 111 TB health care providers who responded to the questionnaire study across TB clinics in New Delhi, India.

    Table S2. Demographics of 300 patients with TB who responded to the questionnaire study across TB clinics in New Delhi, India.

    Table S3. Modeled impact of TB treatment interruptions on health and economic costs in New Delhi, India annually.

    Table S4. Individual subject-level data for Figs. 2 (B to G) and 3 (C and D) and figs. S3A, S4A, S5B, S6, S7 (B and C), S7 (E and F), and S8 (Excel format).

    Data file S1. In vitro design of 3D stomach model.

    Data file S2. Field questionnaire study to inform mode of administration.

    Data file S3. Sensitivity analysis of health and economic model.

    References (6068)

  • The PDF file includes:

    • Materials and Methods
    • Fig. S1. Physical parameters of the GRS as the drug weight increases.
    • Fig. S2. Serial radiographs of the GRS over 1 month in a swine model.
    • Fig. S3. Effect of the GRS on the weight and stomach tissue of swine.
    • Fig. S4. Hall effect sensor acid stability and retrieval using an in vitro stomach model.
    • Fig. S5. In vivo formulations and their corresponding 4-week in vitro drug release profiles of doxycycline hyclate–silicone pills of the 10 g GRS.
    • Fig. S6. In vivo release of rifampicin from the GRS in a swine model.
    • Fig. S7. Field questionnaire results at TB clinics in New Delhi, India.
    • Fig. S8. Field questionnaire results on NG tube deployment at TB clinics in New Delhi, India.
    • Table S1. Demographics of 111 TB health care providers who responded to the questionnaire study across TB clinics in New Delhi, India.
    • Table S2. Demographics of 300 patients with TB who responded to the questionnaire study across TB clinics in New Delhi, India.
    • Table S3. Modeled impact of TB treatment interruptions on health and economic costs in New Delhi, India annually.
    • Legend for table S4
    • Legends for data files S1 to S3
    • References (6068)

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Table S4. Individual subject-level data for Figs. 2 (B to G) and 3 (C and D) and figs. S3A, S4A, S5B, S6, S7 (B and C), S7 (E and F), and S8 (Excel format).
    • Data file S1 (.STL format). In vitro design of 3D stomach model.
    • Data file S2 (.pdf format). Field questionnaire study to inform mode of administration.
    • Data file S3 (.xlsx format). Sensitivity analysis of health and economic model.

Navigate This Article