Research PaperEffect of polymer microstructure on the docetaxel release and stability of polyurethane formulation
Graphical abstract
Introduction
Non-vascular self-expanding metallic stents (SEMS) are used to avoid malignant obstructions of various organs such as esophagus, gastrointestinal tract, pulmonary and urinary tract. But unrestricted growth of tumour often leads to re-occlusion of the passageway [1], [2]. To avoid re-occlusion drug eluting stents (DES) have been investigated as a drug delivery vehicle. Non-biodegradable polymers have been utilized in the manufacture of non-vascular stents [3], [4], [5] as a film covering. Paclitaxel [6], [7] and gemcitabine [1], [8] loaded polyurethane (PU) film covered SEMS has been investigated as a palliation therapy for unresectable malignant obstructions of gastro-intestinal tract.
PUs are one of the most important groups of biomedical polymers. Since the 1960s they have been utilized in the preparation of medical devices, implants and prostheses. Over the years, a concerted effort from researchers in understanding the structure property relationship have widened the application of this polymer class into more sophisticated devices such as orthopaedic implants, neurostimulation devices, blood contacting implants and drug delivery devices [9]. Poly-dimethyl siloxane (PDMS) based PUs are composed of aromatic/aliphatic isocyanate and a PDMS (i.e silicone). An additional diol (chain extender) is included to increase the length of the hard segment and allow microphase separation in the microstructure. The isocyanate portion, along with a chain extender forms the hard segment while the PDMS is the soft portion of the PU. These hard and soft segments are thermodynamically incompatible. Although lack of compatibility (causing phase separated microstructure) is generally considered to improve mechanical properties, PDMS based PUs have reduced tensile strength, extensibility and toughness caused by poor interfacial adhesion between hard and soft domains. To reduce this incompatibility, soft segment diols are generally added in mixed fashion which allows hydrogen bonding interaction between hard and soft segments and reduce the microphase separation [10], [11], [12]. Hard segments contain hydrogen bonded urethane groups which provide strength to the polymer while the soft segments provide the elasticity.
Stability testing of pharmaceutical products provides information on the quality of product under the influence of different conditions of temperature and humidity. It also provides an evidence of the shelf life and storage condition. In the present paper, we focus on the stability aspect of the drug delivery application of PurSil® AL20 TSPU (PUS) for Docetaxel (DTX) delivery to the esophagus through a DES. PUS is a non-biodegradable PDMS based PU and has a tendency to re-orient over the period to a thermodynamically stable microstructure. This property of phase re-organization could potentially change the release behaviour of the DTX over the period under stress (i.e. stability test condition). Drug diffusion especially in the case of phase separated PUs takes place through the tortuous path provided by the soft segments while the hard segments hinder the diffusion physically or chemically by forming a hydrogen bond with the diffusant [13]. Similarly, polymer cross linking [14], [15] and increase in hard segment content [16], [17], [18] have been shown to affect microstructure and diffusion. Strikingly, we found no literature report covering the phase re-organization and its impact on drug release. In addition to the general tests used for the stability assessment viz., physical, chemical and solid state properties we analysed the microstructural changes in PUS using SAXS to elucidate the likely effect of it on the DTX release.
Section snippets
Materials
DTX was obtained from Shanghai Jinhe Bio-Technology Co., Ltd. (Shanghai, China) and PurSil® AL 20 75A TSPU (Fig. 1) was provided by DSM (Biomedical Berkeley, CA, USA). The PUS contains 4,4′-dicyclohexylmethane diisocyanate (HMDI) and chain extender 1,4-butane diol (BD) which together constitute 35% of the total weight. Poly-tetramethylene oxide (PTMO) and PDMS form the mixed soft segment, contributing 44.5% and 20% of the total weight, respectively. PUS is further surface-modified with 0.5% of
Film preparation
Using a Petri plate, blank films were casted [19] from a 5% w/v THF solution of PUS (thickness ∼90 μm). DTX loaded films (F) were prepared by adding 4.76% by weight of DTX. The blank PUS layer was prepared from 5% and 10% w/v THF solution. Thickness of 10% w/v solution film was ∼180 μm. Formulations of the DTX were also prepared in bilayer configuration by agglutinating the blank PUS layer (180 μm thick) to DTX loaded layer using THF. The bilayer configuration facilitates unidirectional release of
Formulation stability under stress condition
Formulation stability was studied from three aspects: (1) physical stability of the film formulation, (2) chemical stability of DTX and its release behaviour, and (3) solid state stability of DTX and PUS microstructural stability.
In terms of physical parameters, weight variation and thickness of the films were determined at the initial and the 3 month time points (Refer S2 in supplementary information). It was observed that the weight variation and the thickness were within the practical
Conclusion
From this case study, it can be concluded that solid state behaviour of the drug as well as microstructural characteristics of the polymer has implications on drug release. Room temperature (25 °C) and moisture resistant container are the preferred conditions for the storage of DTX eluting PUS film covered stent. Although there was re-crystallization even at 25 °C, it does not affect the release behaviour. XRD and SAXS analyses provided an additional insight into the polymer microstructure and
Acknowledgements
The authors would like to acknowledge Mr Kevin Crawshaw (Director, Funds SA, Health Partners Limited, Adelaide) and Ian Harvey Arellano (Ph.D. candidate, University of South Australia Adelaide) for reviewing the manuscript, DSM Biomedical for providing PurSil®AL 20 75A TSPU polymer (PurSil® is a registered trademark of DSM), AINSE Ltd for providing financial assistance (Award No – ALNGRS14054) to perform SAXS and XRD measurements, Ms Rosey van Driel for TEM imaging (Advanced Characterization
References (38)
- et al.
Gemcitabine-releasing polymeric films for covered self-expandable metallic stent in treatment of gastrointestinal cancer
Int. J. Pharm.
(2012) - et al.
Non-vascular drug eluting stents as localized controlled drug delivery platform: preclinical and clinical experience
J. Control. Release
(2013) - et al.
The effect on porcine bile duct of a metallic stent covered with a paclitaxel-incorporated membrane
Gastrointest. Endosc.
(2005) - et al.
In vivo evaluation of 5-fluorouracil-containing self-expandable nitinol stent in rabbits: efficiency in long-term local drug delivery
J. Pharm. Sci.
(2010) Clinical experience and applications of drug-eluting stents in the noncoronary vasculature, bile duct and esophagus
Adv. Drug Deliv. Rev.
(2006)- et al.
Human application of a metallic stent covered with a paclitaxel-incorporated membrane for malignant biliary obstruction: multicenter pilot study
Gastrointest. Endosc.
(2007) - et al.
Paclitaxel-eluting covered metal stents versus covered metal stents for distal malignant biliary obstruction: a prospective comparative pilot study
Gastrointest. Endosc.
(2011) - et al.
Preparation and study of crosslinked polyurethane films to fractionate toluene–n-heptane mixtures by pervaporation
Sep. Purif. Technol.
(2001) - et al.
Free volume and water vapor permeability of dense segmented polyurethane membrane
J. Membr. Sci.
(2006) - et al.
Poly(dimethylsiloxane-urethane) membranes: effect of hard segment in urethane on gas transport properties
J. Membr. Sci.
(2006)
Degradation of paclitaxel and related compounds in aqueous solutions II: nonepimerization degradation under neutral to basic pH conditions
J. Pharm. Sci.
Degradation of paclitaxel and related compounds in aqueous solutions I: epimerization
J. Pharm. Sci.
Modeling and comparison of dissolution profiles
Eur. J. Pharm. Sci.
Properties of polyisobutylene polyurethane block copolymers: 3. Hard segments based on 4,4′-dicyclohexylmethane diisocyanate (H 12 MDI) and butane diol
Polymer
Microstructure of segmented amorphous polyurethanes: small-angle X-ray scattering and mechanical spectroscopy studies
Polymer
Synthesis and characterization of organosiloxane modified segmented polyether polyurethanes
Polymer
Polyurethane-based drug delivery systems
Int. J. Pharm.
Safety evaluation of self-expanding metallic biliary stents eluting gemcitabine in a porcine model
J. Gastroenterol. Hepatol.
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