Research paperPhoto-crosslinked anhydride-modified polyester and –ethers for pH-sensitive drug release
Graphical abstract
Introduction
Polymer-based active agent delivery offers tremendous possibilities for sustained, time-wise controlled and locally administered applications. Oral drug administration is the most common route for systemic delivery of drugs [1], [2]. Some drugs, such as proteins, are labile in gastric acid, and therefore colon targeted drug delivery systems are needed [3], [4], [5]. In addition, some diseases require local drug delivery, such as Crohn′s disease and colon cancer [6], [7]. There are different ways to obtain targeted delivery to the colon, including pH-dependent, time-lag and enzyme-dependent mechanisms [3], [8], [9], [10]. Traditional sustained release devices protect drugs from conditions in stomach and slow down the drug release, whereas controlled release systems locally release the drug at a predetermined rate [11]. Thus, controlled release devices maintain the drug release within the therapeutic window avoiding too low or too high drug concentrations [2].
Polymers are widely studied in medical engineering due to their versatility and possibility to tailor their properties for specific applications. Polymers are modified chemically to obtain materials with desired properties such as suitable mechanical strength, chemical compatibility and degradation [12], [13], [14]. Polymers can also be synthetized to have a low viscosity and photo-crosslinking ability, which enables the preparation of polymer structures under mild conditions. Moreover, a thermally sensitive drug can be mixed with liquid pre-polymer prior to photo-crosslinking, enabling the preparation of drug containing polymer matrices without heat or solvents [12], [13], [15].
Polymers used in controlled drug release are both biostable and degradable [16], [17]. Degradation is the process of polymer chain cleavage and it can be divided into surface and bulk erosion mechanisms [18]. In bulk erosion, the molecular weight is decreasing throughout the polymer and the size of the device remains constant until rapid fragmentation [18], whereas in surface erosion the material is lost from the exterior surface and the size of the device is constantly decreasing [14]. In surface eroding polymers, water penetration into the polymer matrix is slower than the hydrolytic degradation of the material [19]. Surface eroding polymers are usually favored in drug release devices, since the drug is released as the polymer is degrading, and thus larger drug molecules can be used [20]. Bulk degrading polymers on the other hand release the drug by diffusion or leaching, and finally via degradation of polymer matrix [21]. The degradation rate can be modified by copolymerization and functionalization [22]. By chemically modifying the polymer to be more hydrophobic, the hydrolytic degradation rate is lower, whereas enhancing hydrophilicity, the degradation rate is faster [14], [19]. In addition, functionalizing the polymer with hydrolytically labile chemical bonds increases the degradation rate [12].
Polyesters, especially polycaprolatone (PCL), are degrading hydrolytically through bulk erosion [13]. Polyanhydrides also degrade hydrolytically, however, they degrade significantly faster in water and are surface eroding [19]. Anhydride-linkages degrade by base-catalyzed hydrolysis [23] and degradation is pH dependent, being more stable in acidic conditions and more pronounced in basic conditions [19], [24]. Since pH is changing along the gastro intestinal tract, pH-sensitive polymer degradation is a beneficial feature in intestine targeted oral drug delivery. In the stomach, the pH is acidic (pH 1.3–3.0) and in the intestine the pH is close to neutral conditions (pH 5.0–8.0) [8]. pH-sensitive polymers are able to protect sensitive drugs from acidic conditions in the stomach and release the drug in more neutral conditions in the intestine.
Poly(ethylene glycol) (PEG) is a widely researched and utilized polymer in medical applications. Unlike polyesters and polyanhydrides, PEG does not degrade in water. However, it does dissolve in water [25], [26] and small PEG molecules can be removed from the body by metabolization or kidney filtration [26], [27], [28], [29]. Depending on the molecular weight, PEG is a viscous liquid (<1000 g/mol) or solid higher at molecular weights. Polymer molecular weights of under 20 000 g/mol are usually referred to as PEG, while higher molecular weight specimens are usually referred to as poly(ethylene oxide) (PEO).
Several photo-crosslinkable polymers have been developed for medical applications, since the required properties depend upon the application. Photo-crosslinkable polymers such as polyanhydrides [30], polyesters [31], [32], PEGs [33], polyurethanes [34] and their different copolymers [12], [27], [30], [35], [36], [37], [38] have been utilized. Previously, we have researched photo-crosslinkable PCL-based poly(ester-anhydride) precursors for drug release [12], [39]. The degradation of PCL-based (polyester anhydride) networks can be prolonged from days to several weeks by functionalizing with hydrophobic alkenylsuccinic anhydrides. Kim et al. have synthetized linear photo-crosslinkable dimethacrylated PEG-macromers with anhydride linkages [27]. The degradation time for these poly(ether anhydride) networks ranged between 20 min and 2 days depending on the molecular weight of macromer.
In this article, we present a set of new, photo-crosslinkable tree-arm poly(ether anhydride)s and evaluate their potential as drug delivery matrices. The degradation of PEG-based poly(ether anhydride) and PCL-based poly(ester anhydride) networks in different pH conditions as well as drug release from poly(ether anhydride)s has not been previously studied.
The aim in this work was to synthetize polymer networks that have degradation rates of 5 h to 24 h in neutral conditions, since orally administered capsule is likely to arrive in the colon after 5 h of dosing, and the average time for passing through the colon is 20–30 h [4], [9]. In vitro hydrolysis and swelling behavior tests were conducted in different pH conditions to simulate the conditions in gastrointestinal tract. pH-sensitive degradation would be useful in colon targeted drug release of sensitive drugs [8]. Stability in acidic conditions enable the polymer to protect drugs from enzymes and acidic conditions in stomach, and drug would be released as the polymer device is delivered to the intestine and pH is shifting towards neutral conditions.
Section snippets
Materials
Prior to the synthesis, ε-caprolactone (CL, 97%, Sigma-Aldrich) was redistilled. Stannous octoate (SnOct2, 95%), trimethylol propane (TMPE), trimethylolpropane ethoxylate (average Mn 170, 450 and 1014 g/mol), succinic anhydride, methacrylic anhydride, hexane, d-chloroform and dichloromethane were purchased from Sigma-Aldrich and used as received. Photoinitiator TPO-L (ethyl phenyl(2,4,6-trimethylbenzoyl)phosphinate) was from Carbosynth Limited. Model drugs lidocaine and vitamin B12
Results and discussion
The synthesis of PEG-anhydrides is expected to progress similarly as previously reported with PCL-anhydrides [13]. A reaction scheme of synthesis of PEG-anhydrides is presented in Fig. 1.
The chemical structures of macromers were confirmed with 1H NMR, 13C NMR and ATR-IR. 13C NMR was used to monitor the PEG-anhydride synthesis (Fig. 2). As hydroxyl groups react, the carbon in end groups at δ 61 ppm (peak h) react and shifts to δ 64 ppm (peak h′) and a peak around δ 177 pm (COOH-group) appears.
Conclusion
The synthesis of novel, photo-crosslinkable three-arm poly(ether anhydride)s was reported. In vitro hydrolytic degradation of networks and drug release in different pH conditions was studied to evaluate the potential of such polymers for colon targeted drug delivery. The degradation rate of photo-crosslinked poly(ether anhydride)s and poly(ester anhydride) can be controlled by changing the molecular weight and hydrophilicity of macromers. More hydrophilic macromers result in networks, which
Acknowledgements
The authors would like to thank the Finnish Academy of Science and Letters and Jenny and Antti Wihuri Foundation for providing the financial support for this project. Dr. Steven Spoljaric (The University of Melbourne) is thanked for comments on the manuscript. This work has made use of BIOECONOMY infrastructure at Aalto University.
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