Accelerated Degradation of Poly(ε-caprolactone) by Organic Amines

The solid-state degradation of poly(-caprolactone) catalyzed by primary, secondary and tertiary alkylamines was investigated. The degradation process was monitored by weight loss and molecular weight change measured by gel permeation chromatography. Degradation studies were conducted at 37°C in methanol solutions of the alkylamines. Primary alkylamines caused rapid weight loss (i.e., ~90% weight loss in 30 days) that depended on alkylamine concentration, molar ratio of alkylamine to poly(-caprolactone) monomer and alkyl chain length. The secondary alkylamines caused less rapid polymer weight loss (i.e., ~90%) weight loss within 80 days). One tertiary alkylamine (N,N-diisopropylethylamine) showed little catalytic effect while a bicyclic tertiary alkylamine (quinuclidine) was about as catalytic as the primary alkylamines. The degradation products isolated when primary alkylamines were used include both esters and amides indicating that nucleophilic attack by the alkylamines competed with the amine-catalyzed methanolysis reaction. Only ester moieties could be identified in the products from reactions containing secondary and tertiary alkylamines, which indicated that they acted as nucleophilic catalysts. All of the primary alkylamines reduced poly(-caprolactone) molecular weight from about 25,000 to 10,000 within 10 days after which the molecular weight of the remaining solid leveled off even though weight loss continued.     

Microencapsulation of Superoxide Dismutase into Poly(ε-Caprolactone) Microparticles by Reverse Micelle Solvent Evaporation

The aim of this work was to encapsulate superoxide dismutase (SOD) in poly(ε-caprolactone) (PCL) microparticles by reverse micelle solvent evaporation. The concentration of PCL, the hydrophile-lipophile balance (HLB), and concentration of the sucrose ester used as surfactant in the organic phase were investigated as formulation variables. Relatively higher encapsulation efficiency (～48%) and retained enzymatic activity (>90%) were obtained with microparticle formulation made from the 20% (w/v) PCL and 0.05% (w/v) sucrose ester of HLB = 6. This formulation allowed the in vitro release of SOD for at least 72 hr. These results showed that reverse micelle solvent evaporation can be used to efficiently encapsulate SOD in PCL microparticles. Such formulations may improve the bioavailability of SOD.     

Biochar as a sustainable and renewable additive for the production of Poly(ε-caprolactone) composites

Sustainable poly(ε-caprolactone) (PCL) composites can be produced via initiation of polymerization using the surface hydroxyl groups of oxidized biochar nanostructures obtained after liquid-phase exfoliation of biochar. Biochars are stable, renewable, and sustainable carbon-based materials, which in large-scale applications have the potential to mitigate climate change. The biochar used herein is produced by pyrolysis of hardwood waste biomass (e.g. sawdust, branches, bark) and then converted using nitric acid to oxidized biochar (oxbc). Oxbc is directly sonicated in ε-caprolactone to produce the exfoliated analogue (Eoxbc), which is used to promote the ring-opening polymerization of ε-caprolactone. Eoxbc is highly dispersible in this monomer, and thus reactions can be performed under neat conditions. Eoxbc presents sufficient surface hydroxyl groups (?OH) to initiate and facilitate the ring-opening polymerization of ε-caprolactone using tin octoate, organic bases or lipase enzymes as catalysts. The PCL/Eoxbc composites produced present higher crystallinity and increased stiffness when compared to pure PCL. In preliminary studies, Eoxbc also shows a positive effect upon the degradation of PCL under various conditions.     

Surfactant-free microspheres of Poly(ε-caprolactone)/poly (ethylene glyco I )/poly(ε-caprolactone) triblock copolymers as a protein carrier

The aim of this study is to prepare biodegradable microspheres without the use of surfactants or emulsifiers for a novel sustained delivery carriers of protein drugs. A poly(epsilon-caprolactoney poly(ethylene glycol)/poly(epsilon-caprolactone) (CEC) triblock copolymer was synthesized by the ring-opening of epsilon-caprolactone with dihydroxy poly (ethylene glycol) to prepare surfactant-free microspheres. When dichloromethane (DCM) or ethyl formate (EF) was used as a solvent, the formation of microspheres did not occur. Although the microspheres could be formed prior to lyophilization under certain conditions, the morphology of microspheres was not maintained during the filtration and lyophilization process. Surfactant-free microspheres were only formed when ethyl acetate (EA) was used as the organic solvent and showed good spherical microspheres although the surfaces appeared irregular. The content of the protein in the microsphere was lower than expected, probably because of the presence of water channels and pores. The protein release kinetics showed a burst release until 2 days and after that sustained release pattern was showed. Therefore, these observations indicated that the formation of microsphere without the use of surfactant is feasible, and, this the improved process, the protein is readily incorporated in the microsphere.     

Poly(butylcyanoacrylate) and Poly(ε-caprolactone) Nanoparticles Loaded with 5-Fluorouracil Increase the Cytotoxic Effect of the Drug in Experimental Colon Cancer

The clinical use of 5-fluorouracil, one of the drugs of choice in colon cancer therapy, is limited by a nonuniform oral absorption, a short plasma half-life, and by the development of drug resistances by malignant cells. We hypothesized that the formulation of biodegradable nanocarriers for the efficient delivery of this antitumor drug may improve its therapeutic effect against advanced or recurrent colon cancer. Hence, we have engineered two 5-fluorouracil-loaded nanoparticulate systems based on the biodegradable polymers poly(butylcyanoacrylate) and poly(ε-caprolactone). Drug incorporation to the nanosystems was accomplished by entrapment (encapsulation/dispersion) within the polymeric network during nanoparticle synthesis, i.e., by anionic polymerization of the monomer and interfacial polymer disposition, respectively. Main factors determining 5-fluorouracil incorporation within the polymeric nanomatrices were investigated. These nanocarriers were characterized by high drug entrapment efficiencies and sustained drug-release profiles. In vitro studies using human and murine colon cancer cell lines demonstrated that both types of nanocarriers significantly increased the antiproliferative effect of the encapsulated drug. In addition, both nanoformulations produced in vivo an intense tumor growth inhibition and increased the mice survival rate, being the greater tumor volume reduction obtained when using the poly(ε-caprolactone)-based formulation. These results suggest that these nanocarriers may improve the antitumor activity of 5-fluorouracil and could be used against advanced or recurrent colon cancer.KEY WORDS: 5-fluorouracil, colon cancer, poly(butylcyanoacrylate), poly(ε-caprolactone), polymeric nanoparticles     

Poly(ethylene glycol)-poly(ε-caprolactone) Iodinated Nanocapsules as Contrast Agents for X-ray Imaging

Purpose

Synthesis and formulation of iodinated PCL-mPEG nanocapsules as new original blood pool contrast agents for computed tomography.

Methods

PCL-mPEG was synthesized and formulated following the emulsion–solvent diffusion process, in the form of iodinated nanocapsules. Physico-chemical characterization of such nano-materials was performed by DLS and transmission electron microscopy. A stability study of the nanocapsules suspension was followed-up to 3 month. Blood biocompatibility was performed. Finally, the nanocapsules suspension radiopacity was evaluated in vitro then in vivo in mice as micro-CT contrast agent.

Results

In this study, the iodine concentration in nanocapsules suspension was about 70 mgI/mL. Besides, these nanocarriers appeared non-toxic, and stable in suspension. In vivo, i.v. administration of 10 μL/g of mouse body weight of theses nano-particles induced a vascular contrast enhancement of 168 HU and a half-life in blood of 4.2 +/? 0.5 h. Elimination route of these particles appears mainly performed by the liver, without sequestration in spleen and lymph nodes confirming their stealth properties.

Conclusions

This study proposes the first example of iodinated biodegradable polymeric blood pool contrast agent, able to induce an exploitable contrast enhancement. The main advantage of polymeric system compared to lipid ones, lies in their stability and handling, e.g. towards drying for storage.     

Poly (ε-caprolactone) nanocapsules for oral delivery of raloxifene: process optimization by hybrid design approach,in vitro and in vivo evaluation

Abstract

Raloxifene HCl (RLX), a selective oestrogen receptor modulator, has low oral bioavailability (<2%) in humans due to its poor aqueous solubility and extensive first-pass metabolism in gut. In this study, we optimised the method of preparation for poly (ε-caprolactone) (PCL) based nanocapsules of RLX by double emulsion method (w/o/w). A hybrid design approach, Plackett–Burman design followed by rotatable central composite design, was used to arrive at the optimised formulation. The optimised formulation was subjected to in vitro and in vivo evaluation. RLX loaded nanocapsules were spherical in shape with particle size less than 200?nm and high encapsulation efficiency (>80%). RLX-loaded nanocapsules showed 2.1-fold increase in oral bioavailability compared to free RLX. IV pharmacokinetic studies indicated that RLX loaded into nanocapsule had significantly low clearance in comparison with free RLX. Designed nanocapsules showed promise as delivery systems to enhance oral bioavailability and in reducing clearance of raloxifene.     

Improving physicochemical properties and doxorubicin cytotoxicity of novel polymeric micelles by poly(ε-caprolactone) segments

This study constructed a series of novel micelles based on star-shaped amphiphilic copolymers (sPEC/CDs), and aimed to confirm the important role poly(ε-caprolactone) (PCL) segments played to improve the various properties of micelles. sPEC/CDs, consisting of β-cyclodextrin (β-CD) as a core and monomethoxy poly(ethylene glycol) (mPEG) and PCL diblock copolymers as arms, were synthesized by arm-first method. The critical micelle concentrations (CMC) of sPEC/CDs were determined by fluorescence spectrophotometry using pyrene as a probe. 3-(4, 5-dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide and flow cytometry were used to detect drug cytotoxicity and cellular uptake of the doxorubicin-loaded micelles. Rhodamine-123 cellular accumulation was examined to evaluate the polymer action to P-glycoprotein. It was revealed that, once PCL segment was inserted between β-CD and mPEG, the CMC can be significantly decreased, the drug loading capability greatly improved, and the drug resistance of MCF-7/ADR cells effectively reversed. These findings suggest that sPEC/CDs own potential superiority for cancer therapy as drug carriers.     

Comparative Study of Poly (ε-Caprolactone) and Poly(Lactic-co-Glycolic Acid) -Based Nanofiber Scaffolds for pH-Sensing

Purpose

This study aims to develop biodegradable and biocompatible polymer-based nanofibers that continuously monitor pH within microenvironments of cultured cells in real-time. In the future, these fibers will provide a scaffold for tissue growth while simultaneously monitoring the extracellular environment.

Methods

Sensors to monitor pH were created by directly electrospinning the sensor components within a polymeric matrix. Specifically, the entire fiber structure is composed of the optical equivalent of an electrode, a pH-sensitive fluorophore, an ionic additive, a plasticizer, and a polymer to impart mechanical stability. The resulting poly(ε-caprolactone) (PCL) and poly(lactic-co-glycolic acid) (PLGA) based sensors were characterized by morphology, dynamic range, reversibility and stability. Since PCL-based nanofibers delivered the most desirable analytical response, this matrix was used for cellular studies.

Results

Electrospun nanofiber scaffolds (NFSs) were created directly out of optode material. The resulting NFS sensors respond to pH changes with a dynamic range centered at 7.8?±?0.1 and 9.6?±?0.2, for PCL and PLGA respectively. NFSs exhibited multiple cycles of reversibility with a lifetime of at least 15 days with preservation of response characteristics. By comparing the two NFSs, we found PCL-NFSs are more suitable for pH sensing due to their dynamic range and superior reversibility.

Conclusion

The proposed sensing platform successfully exhibits a response to pH and compatibility with cultured cells. NSFs will be a useful tool for creating 3D cellular scaffolds that can monitor the cellular environment with applications in fields such as drug discovery and tissue engineering.

     

Characteristics of felodipine-located poly(ε-caprolactone) microspheres

Felodipine-loaded poly (ε-caprolactone) (PCL) microspheres were prepared by two methods, the conventional emulsion solvent evapouration method and the quenching method. The aim of this work was to investigate the effects of process parameters such as emulsion type, drug loading, molecular-weight of the polymer, types of emulsion stabilizer and dispersed phase solvents, as well as preparation methods. The results show that, when conventional emulsion solvent evapouration method was used, the o/w-method produced smaller mean size and higher encapsulation efficiency compared with the o/o-method. The encapsulation efficiencies increased with an increase in the molecular weight and a decrease in crystallinity of PCL. The size of microspheres varied with the type of emulsion stabilizer used, smaller microspheres with PVA and narrow size distribution with Pol 237. The water solubility of the dispersed phase solvent was one of the critical factors in controlling the encapsulation efficiency and microsphere mean size. When water-soluble solvents such as acetonitrile and ethyl formate were used, the encapsulation efficiencies decreased due to higher evapouration rate. When quenching methods were used, in contrast to the conventional emulsion solvent evapouration method, very narrowly size-distributed but bigger microspheres were obtained.     

Effect of pH on Diclofenac Release from Eudragit RS100® Microparticles. A Kinetic Study by DSC

The present work is aimed at investigating the release of Diclofenac (DCF) from Eudragit RS100T® (RS) microparticles to a biological model membrane consisting of dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV). The microparticles were prepared by the Quasi-Emulsion Solvent Diffusion method (QESD). The drug release was monitored by Differential Scanning Calorimetry (DSC) technique, following the effects exerted by DCF on the thermotropic behaviour of DMPC multilamellar vesicles at different temperatures. DCF affects the transition temperature (T_m) of phospholipid vesicles, causing a m shift towards lower values, which is modulated by the drug fraction entering into the lipid bilayer. Calorimetric measurements were performed at two different pH (4.0 and 7.4) on suspensions of blank liposomes added to weighed amounts of unloaded and DCF-loaded microspheres, as well as to the powdered free drug, after incubation at 37°C. The T_m shifts, caused by the drug released from the polymeric system or by the free drug during incubation cycles, were compared to those caused by a chosen molar fractions of the free drug dispersed directly in the membrane. This in vitro study suggests as the kinetic process involved in drug release is influenced by the amount of drug loaded in the microspheres as well as by the pH value, acting on drug solubility and membrane disorder.     

Colon-targeted celecoxib-loaded Eudragit® S100-coated poly-ϵ-caprolactone microparticles: Preparation,characterization and in vivo evaluation in rats

Context: Celecoxib suffers from low and variable bioavailability following oral administration of solutions or capsules. Recent studies proved that chemoprevention of colorectal cancer is possible with celecoxib.

Objective: This work aimed to tailor colon-targeted celecoxib-loaded microparticles using time-dependant and pH-dependant coats. Estimation of drug pharmacokinetics following oral administration to fasted rats was another goal.

Methods: A 2³ factorial design was adopted to develop poly-?-caprolactone (PCL) celecoxib-loaded microparticles (F1–F8). To minimize drug-percentages released before colon, another coat of Eudragit^® S100 was applied. In vitro characterization of microparticles involved topography, determination of particle size and entrapment efficiency (EE %). Time for 50% drug release (t_50%) and drug-percentages released after 2 hours (Q_2h) and 4 hours (Q_4h) were statistically compared. Estimation of drug pharmacokinetics following oral administration of double-coat microparticles (F10) was studied in rats.

Results: PCL-single-coat microparticles were spherical, discrete with a size range of 60.66?±?4.21–277.20?±?6.10 μm. Direct correlations were observed between surfactant concentration and EE%, Q_2h and Q_4h. The PCL M.wt. and drug: PCL ratio had positive influences on EE% and negative impacts on Q_2h and Q_4h. When compared to the best achieved PCL-single-coat microparticles (F2), the double-coat microparticles (F10) showed satisfactory drug protection; Q_2h and Q_4h were significantly (P?<?0.01) decreased from 31.84?±?1.98% and 54.72?±?2.10% to 15.92?±?1.78% and 26.93?±?2.76%, respectively. When compared to celecoxib powder, F10 microparticles enhanced the bioavailability and extended the duration of drug-plasma concentration in rats.

Conclusion: The developed double-coat microparticles could be considered as a promising celecoxib extended-release colon-targeting system.     

In Vitro and In Vivo Safety Evaluation of Biodegradable Self-Assembled Monomethyl Poly (Ethylene Glycol)–Poly(ε-Caprolactone)–Poly (Trimethylene Carbonate) Micelles

Safety evaluation of self-assembled polymeric micelles is important for biomedical involvement in drug delivery systems in the future. In this study, biodegradable monomethyl poly (ethylene glycol)–poly (ε-caprolactone)–poly (trimethylene carbonate) [MPEG–P(CL-co-TMC)] copolymer was synthesized and characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance analysis, and gel permeation chromatography. MPEG–P(CL-co-TMC) micelles were prepared by self-assembly without any organic solvent. The present study was conducted to assess the safety of blank MPEG–P(CL-co-TMC) micelles both in vitro and in vivo. Particle size (30.09 ± 0.06 nm) and zeta potential (0.067 ± 0.027 mV) of obtained micelles were determined by Malvern laser particle size analyzer. The results of in vitro toxicity evaluation implied that the prepared micelles did not cause hemolysis or severely cell toxicity. Meanwhile, we did not observe any toxic response or histopathological changes in the study of in vivo acute toxicity evaluation and histopathological study of MPEG–P(CL-co-TMC) micelles. In conclusion, the maximal tolerance dose of MPEG–P(CL-co-TMC) micelles (100 mg/mL) by intravenous injection was supposed to be greater than 10 g/kg body weight. Therefore, it might have potential applications in biomedical field. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:305–313, 2014     

Influence of polymers ratio on insulin-loaded nanoparticles based on poly-ε-caprolactone and Eudragit® RS for oral administration

Nanoparticles loaded with two different commercial insulins (Actrapid^®, Novorapid^®) and based on different blends of a biodegradable polyester (poly-ε-caprolactone) and a polycationic non-biodegradable acrylic polymer (Eudragit^® RS) were characterized in vitro. The zeta potential was positive whenever Eudragit^® RS was part of the nanoparticles matrix. The encapsulation efficiency was ~ 96% except for Novorapid^®-loaded particles of poly-ε-caprolactone (only 35%). In vitro release studies revealed a burst release from nanoparticles, which may be of interest for oral delivery. Novorapid-loaded nanoparticles were orally administered to diabetic rats and allowed the glycemia to be decreased when compared with free nanoparticles.     

Paclitaxel Prodrugs with Sustained Release and High Solubility in Poly(ethylene glycol)-b-poly(ε-caprolactone) Micelle Nanocarriers: Pharmacokinetic Disposition, Tolerability, and Cytotoxicity

Purpose

Develop a Cremophor® and solvent free formulation of paclitaxel using amphiphilic block co-polymer micelles of poly(ethylene glycol)-b-poly(?-caprolactone) (PEG-b-PCL) and characterize their release, solubility, cytotoxicity, tolerability, and disposition.

Methods

Hydrophobic prodrugs of paclitaxel were synthesized via DCC/DMAP or anhydride chemistry to overcome the poor loading (<1% w/w) of paclitaxel in micelles of PEG-b-PCL. Micelles were prepared by a co-solvent extraction technique. A micellar formulation of paclitaxel prodrug (PAX7′C₆) was dosed intravenously to rats (10 mg/kg) and compared to Taxol® (paclitaxel in CrEL:EtOH) and PAX7′C₆ in CrEL:EtOH as controls at the same dose. Pharmacokinetic parameters and tissue distribution were assessed.

Results

Paclitaxel prodrugs had solubilities >5 mg/ml in PEG-b-PCL micelles. Resulting PEG-b-PCL micelles contained 17-22% w/w prodrug and were less than 50 nm in diameter. PEG-b-PCL micelles released paclitaxel prodrugs over several days, t_1/2>3 d. Only the 7′derivative of paclitaxel with the shortest acylchain 7′hexonoate (PAX7′C₆) maintained cytotoxic activity similar to unmodified paclitaxel. PAX7′C₆ micelles demonstrated an increase in area under the curve, half-life, and mean residence time while total clearance and volume of distribution decreased.

Conclusions

Paclitaxel prodrugs in PEG-b-PCL micelle nanocarriers augment the disposition and increase tolerability making further studies on tumor efficacy warranted.     

Poly(ε-Caprolactone) Nanocapsules in Carteolol Ophthalmic Delivery

In order to increase the ocular absorption of carteolol, this antiglaucomatous drug was incorporated into either nanoparticles (NP) or nanocapsules (NC). The polymer used was poly(-caprolactone) (PCL). The dosage forms were tested on intraocular hypertensive-induced rabbits. Results are presented as the chronological variations of the intraocular pressure (IOP) in comparison with the commercial aqueous solution (Carteol eye drops). The therapeutic results (decrease in IOP) were much more pronounced with carteolol incorporated into the colloidal carriers than with the commercial eye drops. Further, NC displayed a better effect than NP because the drug was entrapped in the oily core of the carrier, thus more readily available to the eye. The incorporation of the drug into nanocapsules produced a decline in the cardiovascular side effects in comparison with aqueous eye drops, thus showing that the undesired noncorneal absorption was reduced. In conclusion, colloidal suspension made of poly(-caprolactone) could offer a good opportunity for ophthalmic delivery of drugs.     

Biodegradable Pseudolatexes: The Chemical Stability of Poly(D,L-Lactide) and Poly (ε-Caprolactone) Nanoparticles in Aqueous Media

Pseudolatexes of the biodegradable polyesters poly(D,L-lactide) (PLA) and poly(-caprolactone) (PCL) have been developed as potential aqueous coatings for sustained release. Since PLA and PCL are known to hydrolyze, the influence of the surfactant system, temperature, pH, and particle size on the chemical stability of the polymers as aqueous colloidal dispersions was investigated. Pseudolatexes of PLA and PCL formulated with a nonionic surfactant system were the most stable. When these dispersions were stored in unbuffered media for 350 days at 5°C, only small changes in the weight-average molecular weights (M _w) of the polymers were observed. At 37°C there was rapid degradation of both polymers in the dispersions. Arrhenius plots for the degradation of PLA and PCL resulted in a linear relationship for PCL. The nonlinear relationship for PLA was attributed to the polymer being in two different physical states within the 5 to 37°C range which was used for the Arrhenius plots. PCL was in the rubbery state at all temperatures studied. Storage of the pseudolatexes in pH 1.65 buffer at 37°C catalyzed the rates of degradation of both PLA and PCL. However, refrigeration of the pseudolatexes stabilized the polymers even at pH 1.65 for up to 4 months. Particle size had an insignificant effect on PLA and PCL stability in pseudolatexes prepared with either a nonionic or an anionic surfactant system.     

Hydrocortisone-loaded poly(ε-caprolactone) nanoparticles for atopic dermatitis treatment

Atopic dermatitis (AD) is a chronic inflammatory skin condition that affects mostly young infants. The purpose of this research was to achieve a prolonged drug release and the reduction of side effects with hydrocortisone-loaded nanoparticles (NPs), for AD treatment. Poly(ε-caprolactone) (PCL) NPs were prepared by modified solvent displacement method and were characterized in terms of size, potential zeta, morphology, entrapment efficiency (EE), Fourier transform infrared (FT-IR) spectrometry and in vitro permeation studies using Franz cells. Toxicology of this nanosystem was also assessed. The obtained NPs EE showed an increased size and a more homogenous size distribution after loading and were negatively charged. EF was around 62%. In vitro release studies demonstrated a controlled release of drug from the NPs over time. FT-IR analysis showed the system stability for one week. Permeation studies revealed significant differences in the permeation of encapsulated and free hydrocortisone. In vitro toxicity studies showed no effect of drug toxicity after encapsulation. The study seems to indicate that encapsulation of hydrocortisone in PCL NPs could enable a faster control of the disease and a decrease in the side effects associated to the long-term application of corticosteroids.     

Preparation and Characterization of Poly(ε-Caprolactone) Nanospheres Containing the Local Anesthetic Lidocaine

The objective of this work was to develop a modified release system for the local anesthetic lidocaine (LDC), using poly(ε‐caprolactone) (PCL) nanospheres (NSs), to improve the pharmacological properties of the drug when administered by the infiltration route. In vitro experiments were used to characterize the system and investigate the release mechanism. The NSs presented a polydispersion index of 0.072, an average diameter of 449.6 nm, a zeta potential of ?20.1 mV, and an association efficiency of 93.3%. The release profiles showed that the release of associated LDC was slower than that of the free drug. Atomic force microscopy analyses showed that the spherical structure of the particles was preserved as a function of time, as well as after the release experiments. Cytotoxicity and pharmacological tests confirmed that association with the NSs reduced the toxicity of LDC, and prolonged its anesthetic action. This new formulation could potentially be used in applications requiring gradual anesthetic release, especially dental procedures.