Innovative Inclusion Complexes Clotrimazole: Hydroxypropyl-β-Cyclodextrin-Modified Polyurethane Networks as Carriers for Slow Drug Delivery

Abstract

Background/Objectives: Inclusion complexes among drugs and cyclodextrin-modified polymers are a topic of recent interest in pharmaceutical research and industry as they might expand the solubility, bioavailability, and stability of the guest molecules. Polyurethanes derived from cyclodextrins show some biomedical applications. In this study, two cross-linked polyurethane networks based on hydroxypropyl-β-cyclodextrin (HPβCD) and polyethylene glycols (PEG 2000 or PEG 6000) were synthesized with NCO/OH molar ratio 4.3 and 6.3 by the typical two-step polymerization method.

Methods: Inclusion complexes of clotrimazole (CLOT) with two HPβCD-modified polyurethane networks and their corresponding physical mixtures were prepared using kneading methods and physical mixing in a 1:6 weight ratio of CLOT:HPβCD.

Results: Obtained prepolymers, previously end-capped with isocyanate groups forming urethane links with HPβCD, which were confirmed by FTIR analysis. TGA results indicate a slight increase in thermal stability of the prepared complexes. The characteristic endothermic peak of the CLOT at around 145.90 °C did not appear in the DSC curve of the drug-loaded inclusion complexes. The XRD patterns of physical mixtures showed specific peaks corresponding to pure clotrimazole. SEM micrographs confirmed an elliptical/spherical- and plate-shaped particles without phase segregation, indirectly confirming that CLOT is not separately present due to inclusion into HPβCD and entrapment into polyurethane networks. Novel complexes PUR2/HPβCD-CLOT-IC and PUR3/HPβCD-CLOT-IC were applied as drug carriers, and diffusion-controlled kinetics of CLOT release were best described using Higuchi model.

Conclusions: The obtained in vitro results showed surprisingly slow/prolonged clotrimazole release from modified polyurethane networks due to the significant influence of NCO/OH molar ratio and the chosen polyol soft segments chain length with potential in vivo applications.

Introduction

Slow drug release from polymer matrices has garnered attention among researchers due to its target-specificity and the economics of the slow-release strategy.

The slow release of drugs from biocompatible and biodegradable polymer matrices has gained worldwide attention among researchers due to the realization of target-specific controlled delivery of the active ingredient in vivo, as well as the accruing economics of the slow-release technology [1]. Polyurethanes (PURs) are an important group of materials which have biomedical applications such as tissue engineering, orthopedic implants, transdermal patches, and drug delivery carriers. The kinetics of swelling and the sorption performance were observed by Renuka and Sonal [2] for the interpenetrating polymer networks of biodegradable polyurethanes with carbohydrate cross-linkers. They are synthesized biodegradable PURs by using carbohydrates such as glucose (monosaccharide), sucrose (disaccharide) or starch (polysaccharide) as a cross-linker and by varying the NCO/OH and diol/triol/molar ratios.

Currently, chemical modifications of natural carbohydrates as well as cyclodextrins (CDs) have been extensively reported [3]. They are cyclic oligosaccharides containing six (α-cyclodextrin), seven (β-cyclodextrin), or eight (γ-cyclodextrin) glucopyranose units linked by α-(1,4) glycosidic bonds. The structure of CDs molecules resembles truncated cones with the secondary hydroxyl groups located at the wider edge of the ring and the primary groups on the narrower edge. Therefore, CDs have relatively hydrophobic cavities, while their outer surfaces are hydrophilic. These CDs can form reversible host-guest inclusion complexes with a wide variety of inorganic and organic molecules in aqueous solution [4,5]. Hydroxypropyl-β-cyclodextrin (Figure 1), as an alternative with lower toxicity than α-, β-, or γ-CDs, can improve the water solubility of lipophilic compounds, bioavailability, and stability, as well as enable better formulations [6,7].

Polymeric nanoparticles encompass a variety of particles ranging in size from 1 nm to 1000 nm and could be classified as nanocapsules (drug dispersed in a polymer matrix) or nanospheres (drug dispersed in a liquid core encapsulated by a polymer membrane) [4,8]. The polymers used must be biocompatible, easy to obtain, stable, with appropriate biodegradation kinetics, and hypotoxic, while maintaining their properties for a limited time in vivo and with slow degradation of soluble compounds [9,10]. Polymeric nanoparticles show improved encapsulation efficiency compared to other nanoparticles, as they can be controlled by the characteristics of the components that make up the formulation and the method of preparation [11,12,13,14]. The polymer component of the nanoparticle provides additional steric stability and protection against potential changes.

The aggregation of α-, β-, and γ-CDs is a recognized phenomenon as they form self-assembled aggregates in concentrated solutions and bind together by forming a hydrogen bond network, so-called “poly-CD” with optimal configuration “head-to-head/tail-to-tail” orientation of the neighboring CD rings [15,16]. Their mixing with the poly(propylene glycol) or polyethylene glycol (PEG) causes the reversible threading of the CDs molecules along a single polymeric chain, named polypseudorotaxane [15,17,18]. Chemical modification or polymerization of the CD rings is the other possibility that can form CD-based nanostructures. CDs are also used for the formation of different nano-scale drug delivery systems like CD polymers and nanosponges [16]. The 2,3,6-hydroxyl groups of the cyclodextrin ring show different reactivity and can be modified (2,6-OH is the most reactive) [19], which can help their extensive pharmaceutical applications. The main methods for the synthesis of modified CDs are deprotonation, dehydration and condensation. The condensation is the reaction of CDs directly with diisocyanate as a bifunctional linker.

PURs containing CDs have been used to combine synergistically polymer characteristics and inclusion properties of CDs. The lack of good thermal properties, poor solubility, and difficult processing are serious limitations of these materials when they are used alone, but the inclusion of cyclodextrins in the structure of PURs can result in obtaining biodegradable materials with improved mechanical and thermal properties. Therefore, cross-linked polyurethane networks can be obtained by reacting hydroxyl groups of CDs with a diisocyanate, such as isophorone diisocyanate (IPDI, Figure 1), leading to the formation of the urethane linkage (NHCOO). However, few papers are devoted to studying the inclusion capacity of cross-linked CDs into the polyurethane network for pharmaceutical purposes. Cross-linked copolymers based on β-cyclodextrin, polyethylene glycol (PEG, Figure 1) and 4,4′-diphenylmethane diisocyanate were prepared as polymeric solid–solid phase change materials which may be applied in thermal energy storage and temperature control because they exhibit heat storage and release properties due to the phase transition temperature [20]. de Araújo et al. obtained cross-linked polyurethanes with βCD and HPβCD, PEG 400, PEG 1500 or PEG 4000, and TDI, characterized them using FTIR, XRD and TGA methods [5]. They were used as carriers for nifedipine delivery and achieved 80% of nifedipine released during 9.42 h in a slightly acidic solution (pH 6.8). Polyethylene glycol and oligocaprolactone-modified cyclodextrin were prepared by polyaddition cross-linking using isophorone diisocyanate [16]. The cross-linked material was characterized by FTIR, MALDI MS, SEM, TG, DTG, DSC, and dynamic rheology methods. Thermal water swelling and hydrolytic degradation under alkaline conditions revealed the connectivity of the polymer network and the influence of the amount of cross-linked cyclodextrin on the hydrogel properties. Hydrolytically degradable polymer networks with hydrophilic character of levofloxacin as a guest molecule in the cyclodextrin cavity were bonded through physical interactions. A burst release of levofloxacin was observed in the first 50 min (up to 60% of the drug loaded), followed by a sustained release over the next few hours [16].

Clotrimazole (CLOT) (Figure 1), an imidazole derivative, is an antifungal medication that prevents mycotic infections of the gastrointestinal and urinary tract and skin. It has also been reported as an anti-cancer drug based on its ability to inhibit mitochondrial-bound glycolytic enzymes and calmodulin, thereby affording cancer death by autophagy. It is available in numerous conventional dosage forms such as tablets, ointments, creams, vaginal suppositories and solutions, but these conventional dosage forms have not been known to afford slow release of CLOT due to the relatively short residence time [1]. This has resulted in an impairment of the therapeutic efficacy of the drug, necessitating multiple administrations. It is generally safe and poses no risk of acute intoxication when administered topically because of minimal absorption. The primary toxicity risks could be associated with oral lozenges, which can cause gastrointestinal distress (nausea, vomiting), elevated liver enzymes (up to 15% of cases), and potential skin irritation. When clotrimazole is applied topically and locally, toxic effects (i.e., erythema, skin rash, edema, pruritus, urticaria, pelvic cramps, itching, vulva and vagina irritation) may occur due to overdosing [21,22]. Doses up to 100 times the human dose in animal studies were embryotoxic in mice and rats. Otherwise, CLOT is a lipophilic compound with poor aqueous solubility (5.5 μmol/L) and is practically insoluble, requiring effective formulations based on lipid carriers, surfactants, or CDs complexes to enhance its bioavailability [23].

This work aimed to expand the knowledge about cross-linked polyurethane networks based on CDs for pharmaceutical use as a controlled drug delivery system. For this purpose, polyurethanes (PURs) were synthesized by using hydroxypropyl-β-cyclodextrin (HPβCD) as a cross-linker of alicyclic isophorone diisocyanate (IPDI) and two polyethylene glycols (PEG 2000 and PEG 6000). The specific goal of this work was to investigate the influence of different PEG chain lengths, which constitute the soft segments of PUR, by varying the NCO/OH molar ratio on the structural characteristics of the polymer networks, and in particular on the drug release profile and kinetics. This study reported direct, simple, and effective inclusion of CLOT in obtained cross-linked HPβCD-modified polyurethane networks with PEG 2000 or PEG 6000 (PUR2/HPβCD or PUR3/HPβCD, respectively), including their cross-linking, characterization, and application as carriers. In vitro drug release studies were conducted to determine the drug release pattern from two cross-linked HPβCD-modified polyurethane networks.

Based on available data, the potential of such HPβCD-modified cross-linked polyurethane networks for usage as a carrier for prolonged clotrimazole release has not been reported in the literature.

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Reagents

Polyethylene glycols for synthesis (PEG 2000, average Mw~2000 g/mol, PEG 6000, average Mw~6000 g/mol, molecular biology grade) obtained from Sigma Aldrich, Burlington, MA, USA, were dried under vacuum at 80 °C for 12 h before being used as polyols. Hydroxypropyl-β-cyclodextrin 97% (HPβCD), average Mw~1540 g/mol (Figure 1), purchased from Aldrich chemistry (Sigma-Aldrich, Burlington, MA, USA), was used as received.

Clotrimazole, 98.5–100.5% (dry basis) powder (Mw = 344.84 g/mol, aqueous solubility 5.5 μmol/L), as depicted in Figure 1, was purchased from Sigma Chemicals (Steinheim, Germany).

Isophorone diisocyanate (Mw = 222.28 g/mol, 98wt% purity, from Sigma Aldrich, Burlington, MA, USA) (IPDI) (Figure 1) and dibutyltin dilaurate 95% (from Bayer, Leverkusen, Germany) (DBTDL) were used without further purification. The following compounds were obtained from commercial suppliers and used as received: dimethyl formamide, 99.8% (DMF) (Merk-Schuchardt, Hohenbrunn, Germany) and methanol, >95% (Zdravlje, Leskovac, Serbia).

Cakić, S.M.; Ilić-Stojanović, S.S.; Nikolić, L.B.; Nikolić, V.D.; Ristić, I.S.; Marković, G.S.; Nikolić, N.Č. Innovative Inclusion Complexes Clotrimazole: Hydroxypropyl-β-Cyclodextrin-Modified Polyurethane Networks as Carriers for Slow Drug Delivery. Biomedicines 2026, 14, 666. https://doi.org/10.3390/biomedicines14030666

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