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. 2019 Apr 15;11(4):183.
doi: 10.3390/pharmaceutics11040183.

Preparation and Evaluation of Topically Applied Azithromycin Based on Sodium Hyaluronate in Treatment of Conjunctivitis

Qian Chen  1   2 , Chun Yin  3   4 , Jiang Ma  5 , Jiasheng Tu  6   7 , Yan Shen  8   9
Affiliations

Preparation and Evaluation of Topically Applied Azithromycin Based on Sodium Hyaluronate in Treatment of Conjunctivitis

Qian Chen et al. Pharmaceutics. .

Abstract

Azithromycin (AZI) eye drops containing sodium hyaluronate (SH) were developed to improve the bioavailability of AZI. Interaction between AZI and SH in the AZI-SH formulation was investigated by differential scanning calorimetry, X-ray diffraction, and ¹H-nuclear magnetic resonance spectroscopy analyses. Moreover, advantages of using SH as an excipient were investigated by comparing physiological properties and pharmacokinetic behaviors of SH-containing AZI eye drops with that of hydroxypropyl methylcellulose (HPMC)-containing formulation. In addition, safety of the developed AZI-SH eye drops was evaluated by in vitro 3-(4,5-dimethyl-2-Thiazyl)-2, 5-diphenyl-2H-tetrazolium bromide assay (MTT assay) and neutral red uptake assay as well as in vivo eye irritation test and acute toxicity test. The results indicated that AZI formed a complex with SH under a slightly acidic condition. The area under the curve (AUC) of AZI in SH-containing formulation was 1.58-fold higher (P<0.01) than that in HPMC-containing formulation due to the interaction between the amine group of AZI and the carboxyl group of SH, despite of the higher viscosity of HPMC-containing formulation. Safety evaluation showed that AZI-SH eye drops caused no obvious eye irritation and acute toxicity. In conclusion, the developed SH-containing AZI formulation possessing advantages of longer retention time and higher drug availability was a promising drug formulation for topical ocular therapy.

Keywords: azithromycin; bioadhesion; eye drops; ocular bioavailability; safety evaluation; sodium hyaluronate.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Degradation kinetics of azithromycin. A: Apparent first-order plot of azithromycin (AZI) hydrolysis at various pH values. Temperature was 75 °C and ionic strength (I) = 0.3. B: the hydrolysis of AZI at various pH, 75 °C and I = 0.3.
Figure 2
Figure 2
Illustration of interaction between AZI and sodium hyaluronate (SH). A: Differential Scanning Calorimetry (DSC) thermograms; B: X-ray diffraction (XRD) patterns; C: 1H-Nuclear Magnetic Resonance (1H-NMR) spectra. (a) AZI, (b) SH, (c) physical mixture of AZI+SH and (d) AZI-SH complex. D: structure of sodium hyaluronate and azithromycin.
Figure 3
Figure 3
Comparison of the viscosity between AZI-SH formulation, AZI-HPMC formulation, blank SH and blank HPMC.
Figure 4
Figure 4
Concentration-time profiles of AZI in tear fluid after instillation of HPMC preparation and SH preparation in conscious rabbits (n = 5).
Figure 5
Figure 5
Cell viability against 3T3-L1 cells determined by MTT assay (A) and Neutral red uptake (NRU) assay (B). (** P < 0.01).
Figure 6
Figure 6
Evaluation of eye irritation by histopathological examinations of iris, cornea, conjunctiva and sclera.
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