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. 2017 Aug 26:12:6221-6238.
doi: 10.2147/IJN.S140934. eCollection 2017.

Ketoprofen-loaded polymer carriers in bigel formulation: an approach to enhancing drug photostability in topical application forms

Velichka Andonova  1   2 , Petya Peneva  1   2 , George S Georgiev  3 , Vencislava T Toncheva  3 , Elisaveta Apostolova  4 , Zhivko Peychev  5 , Stela Dimitrova  6 , Mariana Katsarova  6 , Nadia Petrova  7 , Margarita Kassarova  1   2
Affiliations

Ketoprofen-loaded polymer carriers in bigel formulation: an approach to enhancing drug photostability in topical application forms

Velichka Andonova et al. Int J Nanomedicine. .

Abstract

The purpose of the study was to investigate the stability and biopharmaceutical characteristics of ketoprofen, loaded in polymeric carriers, which were included into a bigel in a semisolid dosage form. The polymer carriers with in situ-included ketoprofen were obtained by emulsifier-free emulsion polymerization of the monomers in aqueous medium or a solution of the polymers used. The morphological characteristics of the carriers, the in vitro release and the photochemical stability of ketoprofen were evaluated. The model with optimal characteristics was included in a bigel formulation. The bigel was characterized in terms of pH, rheological behavior, spreadability, and in vitro drug release. Acute skin toxicity, antinociceptive activity, anti-inflammatory activity, and antihyperalgesic effects of the prepared bigel with ketoprofen-loaded polymer carrier were evaluated. The carriers of ketoprofen were characterized by a high yield and drug loading. The particle size distribution varied widely according to the polymer used, and a sustained release was provided for up to 6 hours. The polymer mixture poly(vinyl acetate) and hydroxypropyl cellulose as a drug carrier, alone or included in the bigel composition, improved the photostability of the drug compared with unprotected ketoprofen. The bigel with ketoprofen-loaded particles provided sustained release of the drug and had optimal rheological parameters. In vivo experiments on the bigel showed no skin inflammation or irritation. Four hours after its application, a well-defined analgesic, anti-inflammatory, and antihyperalgesic effect was registered. The polymer mixture of poly(vinyl acetate) and hydroxypropyl cellulose as a carrier of ketoprofen and the bigel in which it was included provided an enhanced photostability and sustained drug release.

Keywords: antihyperalgesic effect; antinociceptive activity; biphasic systems; carrageenan-induced edema; emulsifier-free radical polymerization.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Transmission electron microscopy of (A) KP, (B) KP-pVAc, (C) KP-pVAc+CH, (D) KP-pVAc+HPC, (E) KP-pVAc+Cbp, and (F) KP-p(VAc-co-DMAEMC). Note: The selected area electron diffractions of the models are shown in the bottom right corner of the micrographs (A–F). Abbreviations: Cbp, carbomer; CH, chitosan; DMAEMC, 2-(dimethylamino) ethyl methacrylate; HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 2
Figure 2
DTA-TG analysis of (A) KP-pVAc, (B) KP-pVAc+CH, (C) KP-pVAc+HPC, (D) KP-pVAc+Cbp, and (E) KP-p(VAc-co-DMAEMC) (solid line) compared to KP (dotted line) and polymer carriers (dashed line). Abbreviations: Cbp, carbomer; CH, chitosan; DMAEMC, 2-(dimethylamino) ethyl methacrylate; DTA-TG, differential thermal analysis and thermogravimetry; HPC, hydroxy propyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 2
Figure 2
DTA-TG analysis of (A) KP-pVAc, (B) KP-pVAc+CH, (C) KP-pVAc+HPC, (D) KP-pVAc+Cbp, and (E) KP-p(VAc-co-DMAEMC) (solid line) compared to KP (dotted line) and polymer carriers (dashed line). Abbreviations: Cbp, carbomer; CH, chitosan; DMAEMC, 2-(dimethylamino) ethyl methacrylate; DTA-TG, differential thermal analysis and thermogravimetry; HPC, hydroxy propyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 3
Figure 3
ATR-FTIR spectra of KP, KP-pVAc, KP-pVAc+CH, KP-pVAc+HPC, KP-pVAc+Cbp, and KP-p(VAc-co-DMAEMC). Abbreviations: ATR-FTIR, attenuated total reflectance-Fourier transform infrared spectroscopy; Cbp, carbomer; CH, chitosan; DMAEMC, 2-(dimethylamino) ethyl methacrylate; HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 4
Figure 4
In vitro dissolution study of KP-pVAc, KP-pVAc+CH, KP-pVAc+Cbp, KP-pVAc+HPC, and KP-p(VAc-co-DMAEMC), pH 5.5. Abbreviations: Cbp, carbomer; CH, chitosan; DMAEMC, 2-(dimethylamino) ethyl methacrylate; HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 5
Figure 5
Photostability testing of drug-loaded polymeric carriers: forced KP degradation in aqueous media under outdoor daylight. Abbreviations: Cbp, carbomer; CH, chitosan; DMAEMC, 2-(dimethylamino) ethyl methacrylate; HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 6
Figure 6
Characterization of BG30: (A) BG30 formulation obtained after mixing carbopol hydrogel and almond oil organogel; (B) optical microscopy of BG30 at 40× (Leica DMC2900); (C) effect of shearing on the viscosity of BG30 formulation.
Figure 7
Figure 7
ATR-FTIR spectra of BG30-KP and BG30-KP-pVAc+HPC in comparison with these of plain BG30, KP, and KP-pVAc+HPC. Abbreviations: ATR-FTIR, attenuated total reflectance-Fourier transform infrared spectroscopy; HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 8
Figure 8
In vitro dissolution study of BG30-KP, BG30-KP-pVAc+HPC, and KP gel. Abbreviations: HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 9
Figure 9
Photostability testing: forced KP degradation under outdoor daylight. Abbreviations: HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 10
Figure 10
Antinociceptive effect of BG30-KP-pVAc+HPC, BG30-KP, BG30, and KP gel evaluated with “hot plate” test. Notes: *P<0.05 vs BG30-KP-pVAc+HPC; †P<0.001 vs BG30-KP-pVAc+HPC. Abbreviations: HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 11
Figure 11
Effects of BG30-KP-pVAc+HPC, BG30-KP, BG30, and KP gel on carrageenan-induced paw edema in rats. Notes: *P<0.05 vs controls at the first hour; ‡P<0.05 vs controls at the fourth hour. Abbreviations: HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
Figure 12
Figure 12
Effect of BG30-KP-pVAc+HPC, BG30-KP, BG30, and KP gel on carrageenan-induced hyperalgesia in rats. Notes: *P<0.05 vs BG30 at the first hour; **P<0.01 vs BG30 at the first hour; !P<0.05 vs BG30 at the second hour; !!P<0.01 vs BG30 at the second hour; °P<0.01 vs controls at the second hour; †P<0.05 vs BG30 at the fourth hour; #P<0.001 vs controls at the fourth hour; §P<0.01 vs controls at the fourth hour; ©P<0.05 vs controls at the fourth hour. Abbreviations: HPC, hydroxypropyl cellulose; KP, ketoprofen; VAc, vinyl acetate.
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