Formulations for trans-tympanic antibiotic delivery

Abstract

We have developed a drug delivery system for prolonged trans-tympanic antibiotic delivery from a single dose administration. Increased permeability to ciprofloxacin of the intact tympanic membrane (TM) was achieved by chemical permeation enhancers (CPEs--bupivacaine, limonene, sodium dodecyl sulfate); this was also seen by CPEs contained within a hydrogel (poloxamer 407) to maintain the formulation at the TM. The CPE-hydrogel formulation had minimal effects on auditory thresholds and tissue response in vivo. CPE-hydrogel formulations have potential for ototopical delivery of ciprofloxacin for the treatment of acute otitis media (AOM) and other middle ear diseases.

Figure 1

(A) Schematic representation of the in-situ forming antibiotic-loaded P407 gel at the tympanic membrane (TM). Antibiotic diffuses out of the gel, across the TM, and into the infected middle ear cavity. (B) Liquid-to-gel transition of 18% P407-3CPE formulation at 37°C.

Figure 2

Effect of concentration of a single CPE, limonene (LIM), on ciprofloxacin permeation across the chinchilla TM. Inset: Ciprofloxacin permeation in the first 12 hours. 2 mg of ciprofloxacin were originally loaded into each hydrogel. Values are medians ± interquartile ranges (n=4).

Figure 3

Cumulative ciprofloxacin permeation across chinchilla TMs from solutions with single and combination CPEs. SDS = sodium dodecyl sulfate, BPV = bupivacaine, LIM = limonene. 2 mg of ciprofloxacin were loaded into each sample. Inset: Ciprofloxacin permeation profiles in the first 12 hours. Values are medians ± interquartile ranges (n=4).

Figure 4

Cumulative ciprofloxacin release from 18% P407 gels at 37 °C with and without 3CPE. 2 mg of ciprofloxacin were originally loaded into each hydrogel. Values are medians ± interquartile ranges (n=4).

Figure 5

Cumulative ciprofloxacin permeation across the chinchilla TM from gels containing 18% P407 and 3CPE at 37 °C. Inset: Ciprofloxacin permeation profiles in the first 12 hours. 2 mg of ciprofloxacin was originally loaded into each hydrogel. Values are medians ± interquartile range. (n=6).

Figure 6

ABR threshold shifts at a range of frequencies immediately following application of 18% P407 hydrogels containing CPEs. The dotted line indicates where data would lie if there was no change in ABR thresholds compared to pre-application measurements. The grey lines indicate the observed interquartile spread of pre-application control measurements (n = 10). Experimental values are medians ± interquartile range (n = 4).

Figure 7

Photomicrographs of hematoxylin and eosin-stained chinchilla tympanic membrane (TM) sections (n = 2). (A) Normal, untreated TM with distinct stratum corneum (SC) layer (arrow). (B) Infected TM is markedly thicker and exhibits acute inflammation with interstitial edema and cellular infiltration (asterisk). (C, D) TMs exposed to gels containing (C) ciprofloxacin or (D) ciprofloxacin and 3CPE for 7 days showed slight thickening with no or minimal inflammation. EAC = external auditory canal. Magnification, 400X. Scale bar = 20 μm.