Synthesis and characterization of biocompatible polyurethanes for controlled release of hydrophobic and hydrophilic drugs

Design of biocompatible and biodegradable polymer systems for sustained and controlled release of bioactive agents is critical for numerous biomedical applications. Here, we designed, synthesized, and characterized four polyurethane carrier systems for controlled release of model drugs. These polyurethanes are biocompatible and biodegradable because they consist of biocompatible poly(ethylene glycol) or poly(caprolactone diol) as soft segment, linear aliphatic hexamethylene diisocyanate or symmetrical aliphatic cyclic dicyclohexylmethane-4,4′-diisocyanate as hard segment, and biodegradable urethane linkage. They were characterized with Fourier transform infrared spectroscopy, atomic force microscope, and differential scanning calorimetry, whereas their degradation behaviors were investigated in both phosphate buffered saline and enzymatic solutions. By tuning polyurethane segments, different release profiles of hydrophobic and hydrophilic drugs were obtained in the absence and presence of enzymes. Such difference in release profiles was attributed to a complex interplay among structure, hydrophobicity, and degradability of polyurethanes, the size and hydrophobicity of drugs, and drug-polymer interactions. Different drug-polyurethane combinations modulated the distribution and location of the drugs in polymer matrix, thus inducing different drug release mechanisms. Our results highlight an important role of segmental structure of the polyurethane as an engineering tool to control drug release.     

New amoxicillin–poly(lactic acid)‐based conjugates: synthesis and in vitro release of amoxicillin

Long‐term antibiotic treatments are required to cure many diseases. Coupling a bioactive compound to a biocompatible polymer offers, in general, many advantages such as better stabilization of drug and controlled release. The work reported deals with the synthesis of new conjugates based on amoxicillin and oligomers of biocompatible and biodegradable poly(lactic acid), as well as release studies of amoxicillin. These new conjugates were obtained via a Curtius rearrangement or acyl chloride activation, leading to substituted urea or amide bonds between amoxicillin and polymer, respectively. Structures of the conjugates were assessed using Fourier transform infrared and ¹H NMR spectroscopy, double‐detection size exclusion chromatography and electrospray ionization mass spectrometry. In vitro release profiles of amoxicillin in phosphate buffered saline were determined using high‐performance liquid chromatography, and the release rates of amoxicillin from the two conjugates were compared. Copyright © 2010 Society of Chemical Industry     

pH-responsive gelatin microspheres for oral delivery of anticancer drug methotrexate

Multiple unit delivery dosage forms of biodegradable gelatin microspheres containing the anticancer drug methotrexate (GMM) of various mean particle sizes (1–5, 5–10, and 15–20 μm) were prepared by the polymer dispersion technique and were crosslinked with glutaraldehyde. The GMM were coated with biodegradable natural polymers, namely alginate (AGMM) and chitosan (CGMM), which differ in their pH sensitivity, to obtain two different types of pH dependent delivery systems for oral delivery of methotrexate (MTX). The in vitro release profiles of MTX from AGMM and CGMM were determined in simulated gastric medium, intestinal medium, and in media simulating gastrointestinal tract conditions. The effect of the concentration of coating polymer and particle size on the release rate of MTX from both AGMM and CGMM were also studied. Both AGMM and CGMM provided controlled release of MTX following a zero-order release pattern in gastric and intestinal fluids for prolonged periods of time. The release rate of MTX decreased with an increase in concentration of the coating polymer as well as an increase in particle size of the microspheres. Both AGMM and CGMM showed good potential as pH dependent multiple unit delivery systems for the controlled release of MTX in oral administration. © 1995 John Wiley & Sons, Inc.     

Revisiting the time for removing the unloaded drug by dialysis method based on a biocompatible and biodegradable polymer vesicle

Polymer vesicles have been widely explored as drug delivery carriers. However, there are still several notable problems in the determination of the drug loading content (DLC) and the drug loading efficiency (DLE) of the drug delivery vehicles. Presented in this paper is the reconsideration of various important factors in the measurement of the DLC and DLE based on an ‘instant’ biocompatible and biodegradable polymer vesicle which can be directly dissolved in water, with a focus on the study on the time for removing the free drug. Firstly, an anti-cancer drug, doxorubicin (DOX), was successfully encapsulated into a highly biocompatible and biodegradable poly(ε-caprolactone)-block-poly[2-(methacryloyloxy)ethyl phosphorylcholine] (PCL-b-PMPC) diblock copolymer vesicle. Secondly, a specific methodology for removing the unencapsulated drug by dialysis method before the drug release experiment has been established to verify the DLC and the DLE of DOX. A number of important factors have been investigated, such as the period of time for removing the free drug, the temperature and the volume of water outside the dialysis tube, etc. Finally, the DOX release experiment was carried out at pH 5.0 and pH 7.4 with the cumulative release percentages of 55% and 35% after 24 h when the DOX feeding was 1.0 mg. As PCL-b-PMPC vesicles absorb UV light, the DOX encapsulated in polymer vesicles was calculated by subtracting the UV absorbance of vesicle solution from the UV absorbance of DOX-loaded vesicle solution at different DOX feedings of 1.0, 3.0 and 5.0 mg. We also found the appropriate calibration curves at different solution conditions were of great significance for the calculation of DLC and DLE.     

Preparation and application of chitin and its derivatives: a review

Chitin the second most abundant polysaccharide is synthesized by an enormous number of living organisms including fungi and insects. These biopolymers have found many applications in different areas such as: packaging material, membrane for removal of metal ions, dyes and pigments in waste water engineering; anti-cholesterol, fat binding, preservative and food additive in food industry; seed and fertilizer coating, controlled agrochemical release in agriculture; surface treatment, photographic paper in pulp and paper industry; moisturizer, body creams and lotions in cosmetics and toiletries. It has also found wide applications in biomedical such as tissue engineering, drug delivery, wound dressing, scaffolds, cancer diagnosis, etc. The majority of these versatile applications are coming of its non-toxicity, biocompatibility and biodegradability. Chitin is also easily processed as gel, membrane, and nanofiber. This review emphasizes an extensive bibliography of recent basic and applied research and investigations on the aspects of this interesting biopolymer including the recovery, preparation, modification and application of chitin and its derivatives and related compounds. A new class of biocompatible and biodegradable chitin-based polyurethane (PU) elastomer was also introduced and reviewed in this study and it was found that by incorporation of chitin into the PU elastomer backbone, biocompatibility and degradation rate of the final elastomer improved. PUs are one of the synthetic biocompatible polymers with excellent physical and mechanical properties. Combination of this polymer with chitin resulted to a new tailor-made biocompatible and biodegradable polymer with improved properties. These polymers have potential applications in various applications including biomedical.     

In vitro degradation and drug‐release behavior of electrospun,fibrous webs of poly(lactic‐co‐glycolic acid)

Ultrafine fibrous webs of poly(lactide‐co‐glycolic acid) (PLGA) containing the bactericidal antibiotic drug rifampin were prepared by electrospinning, and their properties were investigated for wound‐dressing applications. Because PLGA is a biodegradable and biocompatible polymer, it is one of the best materials for the preparation of wound‐dressing substrates. Through this investigation of PLGA/rifampin electrospun webs, we found that the in vitro degradation reached approximately 60% in 10 days, and the drug release from the webs showed a fast and constant profile suitable for wound‐dressing applications. Also, we observed that both the web‐degradation rate and the drug‐release rate increased as the drug concentration in the PLGA/rifampin electrospun webs and the content level of glycolide units in the PLGA polymer matrix increased. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Studies on preparations and pH/redox responsiveness of zwitterionic nanomicelles of poly[lysine-co-N,N-bis(acryloyl)cystamine-co-dodecylamine]

Poly[L-lysine-co-N,N-bis(acryloyl) cystamine-co-dodecylamine] nanomicelles (NMs) were synthesized through Michael addition terpolymerization in one pot. The NMs showed spheric morphology and uniform size distributions. The NMs had excellent nonspecific protein adsorption ability at pH 7.4. Doxorubicin (DOX) was loaded in the NMs for the investigation of controlled release. The drug delivery results showed that the DOX-loaded NMs displayed apparent pH and reduction sensitivities in response to the environment of tumor cells due to the existence of carboxyl groups, amino groups, and disulfide bonds in the NMs. The NMs were biocompatible, biodegradable, and could be potentially used as drug vehicles in controlled release.     

Reversibly light-responsive micelles constructed via a simple modification of hyperbranched polymers with chromophores

Reversibly light-responsive and biocompatible micelles with an appropriate size were constructed from an amphiphilic spiropyran-containing hyperbranched polyphosphate (denoted as HPHEEP-SP). The polymer was conveniently synthesized based on the modification of a biodegradable hyperbranched polyphosphate with carboxyl-containing spiropyran molecules. HPHEEP-SP can self-assemble to biocompatible micelles with an average diameter of 186.3 nm and a critical micelle concentration of 0.052 mg mL^?1. After 5 min of UV irradiation, the diameter of the micelles decreased gradually to about 100 nm, which is ascribed to the transformation of hydrophobic spiropyran to hydrophilic merocyanine. Subsequent exposure the micelles to visible light, the diameter of the micelles was restored. Model drug coumarin 102 was then encapsulated into the micelles successfully. Light-controlled release and re-encapsulation behaviours were lastly demonstrated by fluorescence spectroscopy. This study provides a convenient way to construct smart nanocarriers for controlled release and re-encapsulation of hydrophobic drugs.     

Preparation and characterization of crosslinked chitosan microspheres for the colonic delivery of 5-fluorouracil

In this work, we attempted to develop a simple and inexpensive colon specific pulsatile drug-delivery system using chitosan microspheres loaded with 5-fluorouracil (5-FU) using an enteric-coated soft gelatin capsule. Chemical crosslinking by glutaraldehyde and interactions between the polymer and the drug were determined by Fourier transform infrared spectral study. Scanning electron microscopy of the microspheres revealed spherical shapes with smooth surfaces. Differential scanning calorimetry studies confirmed the molecular dispersion of the drug in the polymer matrix. Three different formulations (i.e., F1, F2, and F3) were prepared by the variation of the amount of 5-FU. Encapsulation efficiencies of 5.5, 10.8, and 17.9% for drug loadings of 10, 20, and 50%, respectively, were obtained. In vitro release studies were conducted at pH 1.2 and pH 7.4 (to simulate actual gastrointestinal fluid and gastrointestinal tract conditions, respectively). The results indicate that chitosan microspheres released 5-FU in both acidic (60%) and basic pH (40%) conditions, whereas the capsule (filled with chitosan microspheres) showed only 8–10% release in acidic media and nearly 90% in basic media within 12 h. The newly designed pulsatile capsule device could be used for targeting 5-FU to the colon. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Tetracycline release from chitosan/fish‐scale‐based membranes

In this study, we aimed to develop new biocompatible membranes on the basis of chitosan (CHIT) and fish scale powder (ESC) from the species Leporinus elongatus. The possibility of using the uncrosslinked membrane (ESC/CHIT) and membrane crosslinked with sodium tetraborate (ESC/CHIT‐B) for tetracycline release was investigated. The drug‐release kinetics were studied at 30 and 37°C in phosphate buffered saline (pH 7.4). For ESC/CHIT, the drug release was faster, about 6 days, whereas the release time of tetracycline impregnated in ESC/CHIT‐B was about 7 days. The in vitro release behavior of tetracycline from both membranes followed the Peppas and Higuchi kinetic models. The kinetics of drug release from ESC/CHIT were regarded as a coupled diffusion/polymer relaxation mechanism, whereas drug release from ESC/CHIT‐B seemed to be controlled by polymer relaxation. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2014 , 131, 39943.     

Preparation and properties of nanosized biodegradable polymer capsules

This article reports the preparation and properties of nanosized biodegradable polymer capsules synthesized using the electrocapillary emulsification method. The biodegradable polymers used were poly(ε-caprolactone) (PCL), which is a highly biodegradable and biocompatible polymer, and poly(lactide-co-glycolic acid) (PLGA). While the size of the capsules prepared using PCL alone was in the micrometer range, it decreased with an increase in the amount of PLGA added to PCL and eventually reached the nanometer level. When the electrocapillary emulsification applied potential was 2000 V, the sizes of the capsules (PCL:PLGA = 5:5) ranged from 50 to 80 nm. The percentage of glucose trapped in the PCL/PLGA nanocapsules was higher than 80% and the duration of glucose release from the nanocapsules was about two times longer than that from PCL capsules.     

Improvement of thermal properties of biodegradable polymer poly(3‐hydroxybutyrate) by modification with acryloyloxyethyl isocyanate

Poly(3‐hydroxybutyrate) (PHB) is one type of polyhydroxyalkanoates often used as a biomedical material due to its biodegradable and biocompatible nature. However, the mechanical and thermal properties of PHB must be improved before it can be used in a wider variety of biomedical applications. To improve the thermal properties of biodegradable PHB, various reaction conditions were studied. Results demonstrate that reacting PHB with acryloyloxyethyl isocyanate (AOI), a monomer with dual functional groups, produces a modified PHB material with markedly improved thermal properties. The 10% thermal decomposition temperature for PHB modified with 5% AOI was 297°C, which was 26.8°C higher than original PHB. The T_g also increased from 4°C to around 30°C for AOI‐modified materials. Additionally, due to the poly(ester‐urethane) structure and hydrogen bonding of polymer materials, the mechanical properties also improved. Thus, this modified PHB biodegradable polymer may have greater application as a biomedical material due to its enhanced thermal and mechanical properties. POLYM. ENG. SCI., 2012. © 2012 Society of Plastics Engineers     

Poly(aspartic acid) Biohydrogel as the Base of a New Hybrid Conducting Material

In the present study, a composite made of conducting polymer, poly(3,4-ethylenedioxythiophene) (PEDOT), and a biodegradable hydrogel of poly(aspartic acid) (PASP) were electrochemically interpenetrated with poly(hydroxymethyl-3,4-ethylenedioxythiophene) (PHMeDOT) to prepare a new interpenetrated polymer network (IPN). Different cross-linker and PEDOT MPs contents, as well as different electropolymerization times, were studied to optimize the structural and electrochemical properties. The properties of the new material, being electrically conductive, biocompatible, bioactive, and biodegradable, make it suitable for possible uses in biomedical applications.     

UV-assisted synthesis of super-macroporous polymer hydrogels

A facile method to the synthesis of polymer cryogels employing the UV irradiation technique and hydrogen peroxide as initiator is presented. Various cryogels composed of either biocompatible, biodegradable and/or temperature-responsive polymers are synthesized from polymer or monomer precursors. It is found that due to the macroporous structure, the cryogels exhibit a very rapid water uptake and, in the case of temperature-responsive polymers, ultra-rapid volume phase transition. The immobilization of Ag nanoparticles (Ag NPs) into cryogels by two different approaches allows preparation of hybrid systems possessing either very fast release of Ag NPs or very slow release of Ag⁺.     

Grafting polymers from cellulose nanocrystals via surface-initiated atom transfer radical polymerization

Cellulose nanocrystals (CNC) are rod-like nanoparticles extracted from cellulose. Due to their fascinating properties—renewable, biocompatible, non-toxic, biodegradable, excellent mechanical performances, high specific surface area, water dispersible, can be assemble in chiral nematic phases—CNC have shown promise in various fields, including oil recovery, polymer composites reinforcing, hydrogels, aerogels, supercapacitors, energy saving buildings, cosmetics, papermaking, coatings, liquid crystals, and waste water treatment. However, the hydrophilic surface of CNC hinders their broader applications. In this context, surface modification of CNC via polymer grafting can be used to finely tune their surficial properties and endow CNC with a variety of functionalities, such as conductivity, pH or temperature responsiveness, reactivity…In particular, surface-initiated atom transfer radical polymerization (SI-ATRP) is a powerful tool to graft various polymers with a high grafting density and controlled chain length. In this review, the precise control of grafted polymers from CNC via SI-ATRP is first discussed, including issues related to the polymer grafting density, chain length and possibility to perform an asymmetric grafting. Then, the properties and applications of CNC grafted with a variety of polymers are presented. Finally, some challenges and outlook related to the SI-ATRP method applied to the field of CNC is discussed.     

Trisodium trimetaphosphate crosslinked xanthan networks: synthesis,swelling, loading and releasing behaviour

Xanthan (Xan) is a biocompatible and biodegradable polysaccharide with a promising potential as substrate for controlled drug delivery applications. Xan based hydrogels were synthesized in alkaline medium using trisodium trimetaphosphate (STMP) as crosslinking agent. Hydrogels with various crosslinking agent/polymer ratios were synthesized and subsequently characterized by the means of elemental analysis and dynamic swelling degree, model compound loading and releasing behaviour. Two physical parameters (crosslinking density and phosphate charge) are manifesting antagonistic actions by stiffening or disrupting the three-dimensional macromolecular ensemble. The highest swelling degree was obtained using an intermediate STMP:Xan ratio in which case the opposing effects of the two forces are well balanced. The synthesized networks are pH sensitive. In acid and alkaline media the swelling degrees are lower by comparison to neutral pH. The entrapping and releasing behaviour of the newly synthesized xanthan networks were studied using methylene blue as a cationic model molecule. The releasing kinetics present a first-order model.     

Technology assessment of new biodegradable poly(R-3-hydroxybutyrate-co-1,4-butylene adipate) copolymers for drug delivery

New biodegradable biomaterials are attracting a huge interest as alternative to conventional polymers used in the field of drug delivery. In this work, we evaluated the ability of new biocompatible and biodegradable polyesters to form nanoparticles (NPs), and tested their potential carrier properties for controlled release of hydrophilic or lipophilic compounds. Multiblock copolymers derived from poly(R-3-hydroxybutyrate) and poly(1,4-butylene adipate) by microwave-assisted transesterification, having different chemical and physicochemical properties were tested. Nanoprecipitation was applied to obtain NPs with a homogenous size distribution. Oil Red O and calcein were encapsulated as lipophilic and hydrophilic probes, evaluating NP mean size and size polydispersity, surface charge, encapsulation efficiency, and release profile. The release curves were fitted into mathematical models to investigate the release mechanism. NPs stability appeared to be strictly related to storage conditions. The NPs were also successfully autoclaved and their mucoadhesive behavior was assessed by a “mucin-particle method.” © 2018 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47233.     

Surfactant free-poly(lactic-co-glycolic acid) coated artesunate loaded citrate-functionalized hydroxyapatite nanorods as a nanocapsule for improving artesunate delivery and antitumor efficiency

The development of targeted drug delivery systems with controlled drug release and enhanced drug bioavailability has attracted increasing attention as a candidate for clinical applications. We designed biocompatible citrate-functionalized hydroxyapatite nanorods (Cit-HAp NRs) loaded with artesunate (ART) for use in colon cancer therapies. These were then encapsulated into surfactant free PLGA nanoparticles (ART@Cit-HAp NRs/SF-PLGA NPs). The synthesized Cit-HAp NRs, ART-loaded Cit-HAp NRs and ART@Cit-HAp NRs/SF-PLGA NPs were characterized using a variety of comprehensive techniques. An ART loading efficiency of ～92% was observed upon using a 1:10 mass ratio (ART: Cit-HAp NRs). We revealed that the adsorption of ART on Cit-HAp NRs proceeds via a pseudo-second-order adsorption mechanism. The in vitro ART release from the nanocomposites (ART@Cit-HAp NRs/SF-PLGA NPs) exhibits a pH dependent release and the rate of ART release from the ART@Cit-HAp NRs/SF-PLGA NPs was slower than the release from Cit-HAp NRs. The effects of ART@Cit-HAp NRs/SF-PLGA NPs were evaluated in human colon cancer (HCT 116 and Caco-2) cell lines. ART@Cit-HAp NRs/SF-PLGA NPs demonstrated higher anti-proliferation activity compared with free ART. The delivery of ART using Citrate-functionalized hydroxyapatite encapsulated, surfactant free PLGA nanoparticles as a carrier could improve their anti-cancer activities.     

Controlled release mechanisms of sodium benzoate from a biodegradable polymer and halloysite nanotube composite

Multiscale polymeric composites combining a biodegradable matrix with low cost and biocompatible hybrid nanocarriers promise to supply a new generation of multipurpose devices for drug delivery. The aim of this work was to investigate the release mechanisms of sodium benzoate (NaBz ) from halloysite nanotubes (HNTs ) embedded in a biodegradable polymer matrix (poly(?‐caprolactone)). To that purpose, different amounts of NaBz molecules were successfully incorporated into HNTs using a simple environmentally friendly procedure. The resulting HNT‐NaBz nano‐hybrids were then incorporated into a poly(?‐caprolactone) matrix by high energy ball milling at ambient temperature and in dry conditions. Analysis of the resulting composites showed important effects of the HNT‐NaBz nano‐hybrids on the thermal and mechanical properties. Controlled drug release, followed by UV spectrophotometry, was also found to be dependent on the HNT‐NaBz relative fractions. Experimental data were thus analyzed using a modified Gallagher ? Corrigan model and correlated with the nano‐hybrid morphologies. © 2016 Society of Chemical Industry     

基于纤维素模板的聚合物空心微球作为药物载体的性能研究及分析

以羟丙基纤维素为模板材料,分别采用不同的聚合方法制备了2种不同形态和结构的聚合物空心微球--聚N-异丙基丙烯酰胺-co-聚丙烯酸(PNIPAm-co-PAA)微凝胶和聚N-异丙基丙烯酰胺-聚丙烯酸(PNIPAm-PAA)水凝胶微囊。以盐酸阿霉素(Dox)作为模型药物,考察了聚合物空心微球作为药物载体的载药能力和体外释放性能。研究表明,PNIPAm-co-PAA微凝胶、PNIPAm-PAA水凝胶微囊和Dox分子能够通过正负电荷的相互吸引实现有效结合;载药微球具有良好的缓释性能,并对Dox的释放表现出明显的pH值敏感性和温度敏感性。体外细胞毒性实验表明,载药PNIPAm-co-PAA微凝胶、PNIPAm-PAA水凝胶微囊具有很高的抗肿瘤活性,细胞相对存活率均可达20%左右。PNIPAm-co-PAA微凝胶、PNIPAm-PAA水凝胶微囊在作为水溶性药物或蛋白类药物载体方面,具有潜在的应用价值,同时有望应用于木材胶黏剂防腐等。