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

Abstract

Multigram drug depot systems for extended drug release could transform our capacity to effectively treat patients across a myriad of diseases. For example, tuberculosis (TB) requires multimonth courses of daily multigram doses for treatment. To address the challenge of prolonged dosing for regimens requiring multigram drug dosing, we developed a gastric resident system delivered through the nasogastric route that was capable of safely encapsulating and releasing grams of antibiotics over a period of weeks. Initial preclinical safety and drug release were demonstrated in a swine model with a panel of TB antibiotics. We anticipate multiple applications in the field of infectious diseases, as well as for other indications where multigram depots could impart meaningful benefits to patients, helping maximize adherence to their medication.

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(ε-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.