A microneedle platform for buccal macromolecule delivery

Abstract

Alternative means for drug delivery are needed to facilitate drug adherence and administration. Microneedles (MNs) have been previously investigated transdermally for drug delivery. To date, drug loading into MNs has been limited by drug solubility in the polymeric blend. We designed a highly drug-loaded MN patch to deliver macromolecules and applied it to the buccal area, which allows for faster delivery than the skin. We successfully delivered 1-mg payloads of human insulin and human growth hormone to the buccal cavity of swine within 30 s. In addition, we conducted a trial in 100 healthy volunteers to assess potential discomfort associated with MNs when applied in the oral cavity, identifying the hard palate as the preferred application site. We envisage that MN patches applied on buccal surfaces could increase medication adherence and facilitate the painless delivery of biologics and other drugs to many, especially for the pediatric and elderly populations.

Fig. 1. Buccal MN patch concept and fabrication.

(A) Concept for the application of buccal MN patches (i) demonstrates application, (ii) MN patch, (iii) high API density in MN tips, (iv) penetration of surface of buccal mucosa, (v) in the vicinity of microvasculature, (vi) with subsequent API release and systemic absorption. (B) Confocal image of an MN array loaded with FITC-dextran (3 to 5 kDa). (C) MNs are prepared by adding approximately 1 mg of the API (HI or hGH) in powder form to the MN cavities (i) and then using a binding solution (ii) to give mechanical structure to the MN patch (iii). After drying, the MNs are demolded and ready to use (iv). (D) SEM image of an MN. (E) Optical image of MNs loaded with approximately 1 mg of HI and (F) hGH (scale bar, 500 μm).

Fig. 2. Dissolution and marker deposition kinetics of MNs.

(A) HI-loaded polyvinylpyrrolidone (PVP) MNs (1-mm length) before and after insertion for 5, 15, and 30 s to the upper tongue, sublingual, buccal tissue, and palatal regions of a pig. Control MN patches were placed on the tissue without any external force for 30 s. Scale bars (white line), 1 mm. (B) Normalized percentage of radiant efficiency resulting from the fluorescent excitation of human and pig tissue postinsertion of Texas Red–loaded PVP MNs loaded for defined time intervals. (C) Radiant efficiency of a piece of human buccal tissue after placement of a control and three MN patches at defined times. (D) Representative histological image of a HI-loaded MN penetrating into human buccal tissue.

Fig. 3. MN-mediated delivery of HI and hGH in swine.

HI quantification from swine’s blood plasma at set time points after applying an HI-loaded PVP MN array onto the tongue (A) and sublingually (B) (n = 3, mean ± SE). HI concentration in swine blood plasma after applying HI-loaded PVP-based (C) or sorbitol-based (D) MN array onto the palatal area and buccal tissue or delivering a subcutaneous (SubQ) injection of a solution with dissolved HI-loaded MN tips (n = 3, mean ± SE). (E) Normalized blood glucose change observed after administration of HI subcutaneously and via MNs in the buccal tissue and palatal area of pigs (n = 3, mean ± SE). hGH concentration in swine blood plasma following delivery subcutaneously of a solution with dissolved hGH-loaded MN tips and via the application of hGH-loaded PVP baseplates or MNs in the (F) palate and (G) buccal tissue, and when applying hGH-loaded sorbitol MNs in the buccal tissue (H) of Yorkshire pigs (n = 3, mean ± SE).

Fig. 4. Stability of HI and hGH when stored under different conditions.

(A) Percentage of HI dimer formation observed in the MN tips after storing the PVP and sorbitol MN arrays under different conditions at the day of fabrication and after 1, 2, and 3 months (n = 3, mean ± SD). Dashed line is at 0.5% of dimer. (B) Percentage of HI recovered from the MN tips of arrays stored under different conditions for 3 months. (C) Percentage of hGH dimer formation observed in the MN tips after storing the MN arrays under different conditions for up to 3 months (n = 3, mean ± SE). Missing bars are due to masking of the hGH peak within the PVP. (D) hGH quantified from the MN tips of arrays stored under different conditions for 3 months. (E) Purity of the hGH loaded in the MN tips of arrays stored under different conditions for 3 months.

Fig. 5. Human acceptability trial of MN patches in the oral cavity.

(A) Images of the application site in swine after removal of the MN patch. (B) Time recorded by a time sensor to achieve a 10-N force when applying baseplates in different tissues using the custom-made applicator in three human volunteers (n = 15). (C) Preferred site of buccal patch application reported by the participants in the questionnaire (n = 100). Note that multiple selections were allowed. (D) VAS score reported by the participants of the study for baseplate and MN patches in the six different locations (n = 100). Photo credit: Ester Caffarel-Salvador, MIT.