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Mucoadhesive Hydrogels for Buccal Drug Delivery in Vitro-In Vivo

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Mucoadhesive Hydrogels for Buccal Drug Delivery in Vitro-In Vivo European Journal of Pharmaceutics and Biopharmaceutics 142 (2019) 498–505 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb Research paper Mucoadhesive hydrogels for buccal drug delivery: In vitro-in vivo correlation study T Randi Angela Bausa, Forouhe Zahir-Jouzdania,b, Sarah Dünnhaupta, Fatemeh Atyabib, ⁎ Andreas Bernkop-Schnürcha, a Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, Innsbruck, Austria b Department of Pharmaceutical Nanotechnology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14174, Iran ARTICLE INFO ABSTRACT Keywords: Aim: It was the aim of this study to assess in vitro methods for the characterization of mucoadhesive hydrogels IVIVC for their potential to predict the residence time on human buccal mucosa. Hydrogel properties Methods: Mixtures of hydrogels comprising hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose Mucosal residence time (CMC), xanthan gum (XTGM), hyaluronic acid sodium salt (HA), sodium alginate (ALG), carbopol (CP) as well as Buccoadhesion polycarbophil (PCP) and porcine mucus were analysed for relative rheological synergism. Furthermore, hy- Texture analysis drogels were characterized for their texture and mechanical properties. For the assessment of mucoadhesive Tensile studies strength of formulations tensile studies were performed on porcine buccal mucosa. To facilitate a direct com- parability of data the residence time of stained hydrogels was determined ex vivo on porcine buccal mucosa and in the oral cavity of volunteers. Results: The extent of relative rheological synergism was in good agreement with data from in vivo residence time studies. Results of tensile studies were further effected by textural properties of hydrogels leading to a restricted correlation with data from the in vivo experiment. The resistance towards removal by artificial saliva flow ex vivo revealed the highest correlation to the in vivo experiment with increasing mucosal residence time in the rank order CP < HEC, HA, ALG, PCP < CMC < XTGM. Conclusions: This overview of measurement principles to predict the residence time of hydrogels for buccal application in humans may be a potent tool for the development of semisolid intraoral formulations. 1. Introduction The variability of methods including discrepancies in polymer con- centration, test parameters, source and type of mucosal tissues or mucin The usage for the treatment of periodontal as well as fungal or in- restricts the comparability of studies. Fundamental differences in the flammatory diseases in the oral cavity gives semisolid dosage forms a underlying measurement principle and validity of results for either the vital role in buccoadhesive drug delivery. Besides the more acceptable cohesiveness of the gel itself or the interface between mucosa and do- mouth feel in comparison to solid dosage forms, syringability and ease sage form need to be taken into consideration [7]. Approaches to cor- of placement in the periodontal pocket are key advantages of semi- relate results obtained by rheological measurements with varying de- solids. However, the restricted ability to deliver a measured dose of signs for tensile studies and textural properties of hydrogels showed so drug in comparison to unit dosage forms and the poor retention on the far limited success [8,9]. Moreover, a lack of in vivo data for correlation site of application are major drawbacks of these formulations [1].In makes an interpretation of in vitro data difficult. Needleman et al., for order to prolong the mucosal residence time various mucoadhesive instance, performed ex vivo adhesion tests on hamster cheek pouch polymers have been incorporated in semisolid delivery systems [2]. The mucosa in organ culture and compared the obtained results with those extent of mucoadhesive properties of these formulations, mainly hy- obtained in humans. The evaluation of three hydrogels revealed the drogels, was assessed by means of different measurement principles. same rank order for adhesion time but strongly deviating absolute re- Especially rheological as well as tensile studies were employed to es- sidence times for all formulations [10,11]. tablish a ranking of polymers for their mucoadhesive properties [3–6]. Aiming to correlate ex vivo buccoadhesion with in vivo results on cell ⁎ Corresponding author at: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. E-mail address: [email protected] (A. Bernkop-Schnürch). https://doi.org/10.1016/j.ejpb.2019.07.019 Received 21 March 2019; Received in revised form 6 June 2019; Accepted 18 July 2019 Available online 19 July 2019 0939-6411/ © 2019 Elsevier B.V. All rights reserved. R.A. Baus, et al. European Journal of Pharmaceutics and Biopharmaceutics 142 (2019) 498–505 level Kokisch et al. tested four different polymer dispersions for their Table 1 residence time. Using a direct staining method on extracted human Characteristics of employed polymers and hydrogel formulations. Results for buccal cells bioadhesive properties from ex vivo studies could be con- complex shear modulus were obtained from frequency sweep measurement at a firmed in vivo. However, the extent of adhesive interactions in vivo was frequency of 1 Hz (means of at least three experiments ± standard deviation). not reflected by the ex vivo ranking of polymers. Furthermore, dis- Polymer Molecular Charge at Concentration [% Complex modulus crepancies to previous studies were referred to a lack of sensitivity of mass [kDa] pH 6.8 w/v] [Pa] the employed staining method [12]. Beyond these limitations, the usage HEC 300 non-ionic 6.5 60.20 ± 3.86 of human buccal cells for ex vivo studies may impede the broad appli- CMC 450 anionic 3.0 62.04 ± 2.80 cation of this method. XTGM 1000 anionic 2.5 72.67 ± 3.49 The establishment of valid in vitro methods for the evaluation of HA 1500–1800 anionic 1.5 63.87 ± 11.15 mucoadhesive properties of semisolid formulations on the intraoral ALG 100–200 anionic 6.0 79.86 ± 10.05 mucosa highly correlating with results obtained in vivo is therefore CP 3000 anionic 0.5 638.31 ± 15.27 PCP 3000 anionic 0.5 188.28 ± 5.00 urgently needed. In particular, the development of mucoadhesive lo- zenges and mouthwashes for the treatment of sore throat or alleviation of symptoms of dry mouth syndrome will tremendously benefit from in 2.3. Intestinal mucus collection and purification vitro methods of high predictive power for the performance of intraoral formulations in humans [13,14]. Porcine small intestinal mucus used for this study was collected and Referring to the broad range of established in vitro test systems to purified according to a previously described method [16,17]. There- assess different aspects of mucoadhesion in the oral cavity, the objec- fore, small intestine from freshly slaughtered pigs was cut in pieces of tive of the present study was an evaluation of their predictability for the 15 cm and opened longitudinally. Sections containing chime were re- in vivo performance. Apart from the determination of rheological sy- moved and discarded. Mucus was collected by gently scraping off the nergism, this work covers the swelling and textural properties of hy- mucosa and stirred (≤40 rpm) in 0.1 M sodium chloride (NaCl) for 1 h drogels comprising polymers of fundamentally different polymeric at 4 °C at a ratio of 1 g of mucus in 5 mL of NaCl solution. The obtained backbone, charge and molecular mass. Using porcine buccal mucosa, mixture was centrifuged for 2 h at 10,400 g at 10 °C (SIGMA 3-18KS, tensile and flow retention studies were optimized for correlation to in Sigma Laborzentrifugen GmbH, Osterode am Harz, Germany) and the vivo conditions. Residence time studies in five healthy volunteers served supernatant as well as the granular material on the bottom were re- to interpret in vitro experiments for their validity for the in vivo per- moved. The resulting pellet was resuspended in NaCl 0.1 M at a ratio of formance. 1 g of mucus to 2.5 mL of NaCl and stirred (≤40 rpm) for 1 h at 4 °C. After centrifugation for 1 h at 10,400 g at 10 °C the supernatant was 2. Materials and methods removed and the purified mucus was collected for rheological mea- surements. 2.1. Materials To characterize purified mucus for its water content a gravimetric analysis was performed. Therefore, 500 mg of the resulting mucus was Polymers employed in this study were kindly donated from the weighted in a pre-dried petri dish, dried under reduced pressure over manufacturers. Hydroxyethyl cellulose (HEC) (Natrosol® 250 G 42 h (Christ Gamma 1–16 LSC freeze dryer, Martin Christ PHARM) was a gift from Ashland Industries Netherland B.V., Gefriertrocknungsanlagen GmbH, Osterode am Harz, Germany) and the Zwijndrecht, Netherlands, sodium carboxymethyl cellulose (CMC) dry weight of the sample was measured. (Cekol® 4000) from CP Kelco Oy, Äänekoski, Finland, xanthan gum (XTGM) (Xanthan FFOC) from Jungbunzlauer Austria AG, Vienna, Austria, hyaluronic acid sodium salt (HA) (molecular weight 2.4. Rheological measurements 1.50–1.80 MDa) from GfN Herstellung von Naturextrakten GmbH, Wald-Michelbach, Germany, sodium alginate (ALG) To characterize hydrogels for their rheological properties a plate- (Manucol® LKX MCLLKX) from FMC International, Health and plate rheometer (Thermo Scientific™ HAAKE™ MARS™ rheometer, Nutrition, Cork,
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