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.     

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.     

Antibacterial electrospun poly(ɛ-caprolactone)/ascorbyl palmitate nanofibrous materials

The one-step incorporation of ascorbyl palmitate (AP), a widely used derivative of vitamin C, into nanofibrous mats of poly(?-caprolactone) (PCL) by electrospinning was demonstrated. The incorporation of AP was attested by IR spectroscopy; the AP content was determined by thermogravimetric analysis (TGA); and the surface composition of the mats: by X-ray photoelectron spectroscopy (XPS). The possibility for deposition of silver nanoparticles onto PCL/AP mats using the ability of AP to reduce silver ions was demonstrated. The silver content was determined by TGA, and the silver nanoparticles were observed by transmission electron microscopy (TEM). The nanoparticles were composed of elemental silver, as verified by XPS analyses. The UV-vis spectrophotometric analyses, study on quenching of the free 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and microbiological tests against the pathogenic microorganism Staphylococcus aureus showed that AP preserved its stability and its antioxidant and antibacterial activity when incorporated in the nanofibrous mats.     

Efficacy of methotrexate-loaded poly(ε-caprolactone) implants in Ehrlich solid tumor-bearing mice

Abstract

Context: Methotrexate (MTX) is used in the treatment of malignancies; however, its clinical application is limited by its toxic dose-related side effects. An alternative to overcome the toxicity of the MTX in healthy tissues is the design of an implantable device capable of controlling the delivery of this drug for an extended period within the tumor site.

Objective: To develop methotrexate-loaded poly(ε-caprolactone) implants (MTX PCL implants) and to demonstrate their efficacy as local drug delivery systems capable of inhibiting Ehrlich solid tumor bearing mice.

Materials and methods: MTX PCL implants were produced by the melt-molding technique and were characterized by FTIR, WAXS, DSC and SEM. The in vitro and in vivo release of MTX from the PCL implants was also evaluated. The efficacy of implants in inhibiting tumor cells in culture and the solid tumor in a murine model was revealed.

Results and discussion: The chemical and morphological integrity of the drug was preserved into the polymeric matrix. The in vitro and in vivo release processes of the MTX from the PCL implants were modulated by diffusion. MTX diffused from the implants revealed an antiproliferative effect on tumor cells. Finally, MTX controlled and sustained released from the polymeric implants efficiently reduced 42.7% of the solid tumor in mice paw.

Conclusion: These implantable devices represented a contribution to improve the efficacy and safety of chemotherapy treatments, promoting long-term local drug accumulation in the targeted site.     

Functionalized three-arm poly(ε-caprolactone) maleic acid microspheres for controlled protein release

Introduction

The objective of this work was to fabricate a novel class of protein carriers from double-bond-functionalized multiarm poly(ε-caprolactone) maleic acid (PGCLM) microspheres and to examine protein sustained-release profiles in vitro over a period of a few months.

Methods

The double-emulsion technique was used to formulate terminal functionalized three-arm PGCLM microspheres having three different types of functional groups (-OH, -COOH, and -C = C-), and one of the functional groups (>C = C< bonds) was used to formulate surface-crosslinked microspheres (NPGCLM). Ovalbumin (OVA) was used as a model protein for examining its release profiles from PGCLM and NPGCLM microspheres in 0.1M phosphate-buffered saline (PBS) at 37°C. These microspheres were also characterized in terms of their morphology, size distribution, and stability.

Results

The mean size of fabricated microspheres ranged from 21.9µm to 51.1µm. An OVA protein was successfully encapsulated into these biodegradable PGCLM microspheres with loading efficiency ranging from 34.2% to 46% (w/w), depending on the ratio of PGCLM to polyvinyl alcohol (PVA) stabilizer. Depending on the polymer to PVA stabilizer ratio, the cumulative OVA release % (w/w) in 0.1M PBS at 37°C ranged from 30% to 40% within 50 days. We further demonstrated the availability of the functional >C = C< bonds on the surface of PGCLM microspheres, which we expect could be used for either covalent binding of bioactive agents or imparting different chemical characteristics onto the surface of the microspheres for broadening of their applications.

Discussion/Conclusion

A method for the preparation of biodegradable microspheres from water/oil emulsion of multiarm and functionalized poly(ε-caprolactone) [PGCL, PGCLM, and NPGCLM] was reported as a potential means of developing injectable therapeutic formulations for drugs. The most unique aspect of these biodegradable microspheres is the availability of two functional groups (>C = C< bonds and -COOH pendant group) on the microsphere surface for potential additional chemical or/and biochemical modifications, such as the formation of crosslinked network surface structure. The incorporation of terminal hydrophilic functional maleic acid into hydrophobic three-arm PGCL chains significantly improved the loading efficiency of OVA and its release profiles. These functionalized biodegradable microspheres may provide a good alternative to linear aliphatic polyester-based drug delivery systems and resulted in development of a long-acting, injectable drug carrier for sustained drug release over a period of few months.     

Silk coating on poly(ε-caprolactone) microspheres for the delayed release of vancomycin

The treatment of osteomyelitis remains a challenge for orthopaedic surgeons. Controlled release of vancomycin from biodegradable microspheres is a promising method for eliminating infection. However, the large initial burst release may make it difficult to maintain the local vancomycin concentration superior to minimum inhibitory concentration for several weeks. The aims of this study were to explore applications of the silk fibroin (SF) as an aqueous coating material for vancomycin-loaded poly(ε-caprolactone) (PCL) microspheres, and investigate the effects of silk coating on in vitro drug release. Examinations of particle size analyses, vancomycin content, Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and in vitro drug release were performed. The results showed that silk coating could reduce the large initial burst release and retard the vancomycin release. Therefore, we suggest that the SF could be used as an aqueous coating material for vancomycin-loaded PCL microspheres and prolonged the drug release. SF coating on vancomycin-loaded PCL microspheres may be considered as an effective approach to prolong the drug release and improve the anti-infection effects.     

Comparative studies of poly(ε-caprolactone) and poly(D,L-lactide) as core materials of polymeric micelles

Polymeric micelles have been successfully used to deliver a variety of therapeutic agents. Nonetheless, several limitations and considerations must be clarified and well-studied to achieve the highest therapeutic effect. In this study, a series of methoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) and methoxy poly(ethylene glycol)-block-poly(D,L-lactide) (PEG-b-PLA) with varying molecular weight (MW) of hydrophobic core segment were synthesized. These block copolymers can form micelle with PCL or PLA as core-forming blocks and PEG as a coronal material. The effect of MW on micelle size and critical micelle concentration (CMC) was studied. DOX (DOX) was encapsulated inside the micelle core. Drug-loading content and size of micelles were studied. Drug release studies inside cells were evaluated by confocal laser scanning microscopy. In summary, the PLA core which is less hydrophobic than PCL showed higher CMC, smaller micelle size and faster DOX release inside nucleus.     

Silk coating on poly(ε-caprolactone) microspheres for the delayed release of vancomycin

The treatment of osteomyelitis remains a challenge for orthopaedic surgeons. Controlled release of vancomycin from biodegradable microspheres is a promising method for eliminating infection. However, the large initial burst release may make it difficult to maintain the local vancomycin concentration superior to minimum inhibitory concentration for several weeks. The aims of this study were to explore applications of the silk fibroin (SF) as an aqueous coating material for vancomycin-loaded poly(ε-caprolactone) (PCL) microspheres, and investigate the effects of silk coating on in vitro drug release. Examinations of particle size analyses, vancomycin content, Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and in vitro drug release were performed. The results showed that silk coating could reduce the large initial burst release and retard the vancomycin release. Therefore, we suggest that the SF could be used as an aqueous coating material for vancomycin-loaded PCL microspheres and prolonged the drug release. SF coating on vancomycin-loaded PCL microspheres may be considered as an effective approach to prolong the drug release and improve the anti-infection effects.     

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.     

Biodegradable poly(ɛ-caprolactone)–poly(ethylene glycol) copolymers as drug delivery system

Poly(?-caprolactone)–poly(ethylene glycol) (PCL–PEG) copolymers are important synthetic biomedical materials with amphiphilicity, controlled biodegradability, and great biocompatibility. They have great potential application in the fields of nanotechnology, tissue engineering, pharmaceutics, and medicinal chemistry. This review introduced several aspects of PCL–PEG copolymers, including synthetic chemistry, PCL–PEG micro/nanoparticles, PCL–PEG hydrogels, and physicochemical and toxicological properties.     

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.     

Pharmacokinetic and Tissue Distribution of Orally Administered Cyclosporine A-Loaded poly(ethylene oxide)-block-Poly(ε-caprolactone) Micelles versus Sandimmune® in Rats

Pharmaceutical Research - We have previously reported on a polymeric micellar formulation of Cyclosporine A (CyA) based on poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO5K-b-PCL13K)...     

Polysorbate 80 coated poly (ɛ-caprolactone)-poly (ethylene glycol)-poly (ɛ-caprolactone) micelles for paclitaxel delivery

Physicochemical properties of two anhydrates (α-form and β-form) and three hydrates (hemihydrate, monohydrate and sesquihydrate) of sitafloxacin (STFX), a novel fluoroquinolone antibiotic, were investigated and correlated with the crystal structure of each crystalline form. STFX sesquihydrate showed larger weight change between 1% and 95% relative humidities (RHs) than other crystalline forms. In the crystal of sesquihydrate, STFX molecules form a channel structure where water molecules exist. Contrary to sesquihydrate, water molecules in a monohydrate are located in well-defined and isolated crystallographic sites. The β-form exhibited the worst photostability than any other forms under the irradiation of a D65 lamp. The intramolecular hydrogen bonding in the β-form caused a red shift on the solid-state UV spectrum by prolonging the conjugation system of the quinolone ring, resulting in greater absorption of photoenergy and consequent degradation. Solubility is also affected by the crystalline structure. Standard free energy of the formation of STFX molecule in each crystalline form and/or lattice energy binding STFX molecules to retain the crystal structure might cause a difference in solubility.     

Preparation of Tacrolimus loaded micelles based on poly(ɛ-caprolactone)-poly(ethylene glycol)-poly(ɛ-caprolactone)

Self-assembled polymeric micelles are widely applied in drug delivery system. In this study, Tacrolimus (FK506) loaded micelles were prepared based on biodegradable poly(?-caprolactone)-poly(ethylene glycol)-poly(?-caprolactone) (PCEC) copolymers. Micelles were prepared by self-assembly of triblock copolymer PCEC in distilled water triggered by its amphiphilic characteristics. Drug loading and encapsulation efficiency were determined by adjusting the weight ratio of FK506 and PCEC. The particle size distribution and variation of obtained micelles were determined using Malvern laser particle size analyzer, while the spherical geometry was observed on transmission electron microscope (TEM), and the crystallographic assays were fulfilled by X-ray diffractometer (XRD). Besides, in vitro release profile demonstrated a significant difference between rapid release of free Tacrolimus and much slower and sustained release of FK506 loaded micelles. These results suggested that we have successfully prepared Tacrolimus loaded micelles in an improved method which is safer and more efficient. The prepared micelles might be potential carriers for Tacrolimus delivery in immunosuppressive therapy.     

Nifedipine encapsulated core-shell type nanoparticles based on poly(γ-benzyl L-glutamate)/poly(ethylene glycol) diblock copolymers

The diblock copolymers based on PBLG and PEO (GE) were synthesized and characterized. Nanoparticles showed spherical shape from the observations of TEM and approved core-shell structure. Drug contents were increased with use of higher initial drug concentration and higher Mw of GE. Nifedipine (NFD) release rate was slower in longer PBLG chain length and higher NFD contents than short PBLG chain length and lower drug contents of NFD due to the hydrophobic interaction between PBLG domain and NFD.     

In situ forming biodegradable poly(ε-caprolactone) microsphere systems: a challenge for transarterial embolization therapy. In vitro and preliminary ex vivo studies

Background: In situ forming biodegradable poly(ε-caprolactone) (PCL) microspheres (PCL-ISM) system was developed as a novel embolic agent for transarterial embolization (TAE) therapy of hepatocellular carcinoma (HCC). Ibuprofen sodium (Ibu-Na) was loaded on this platform to evaluate its potential for the treatment of post embolization syndrome.

Methods: The influence of formulation parameters on the size/shape, encapsulation efficiency and drug release was investigated using mixture experimental design. Regression models were derived and used to optimize the formulation for particle size, encapsulation efficiency and drug release profile for TAE therapy. An ex vivo model using isolated rat livers was established to assess the in situ formation of microspheres.

Results: All PCL-ISM components affected the studied properties and fitting indices of the regression models were high (Radj² = 0.810 for size, 0.964 encapsulation efficiency, and 0.993 or 0.971 for drug release at 30 min or 48 h). The optimized composition was: PCL = 4%, NMP = 43.1%, oil = 48.9%, surfactant = 2% and drug = 2%. Ex vivo studies revealed that PCL-ISM was able to form microspheres in the hepatic arterial bed.

Conclusions: PCL-ISM system provides a novel tool for the treatment of HCC and post-embolization syndrome. It is capable of forming microspheres with desirable size and Ibu-Na release profile after injection into blood vessels.     

Treatments of paclitaxel with poly(vinyl pyrrolidone) to improve drug release from poly(ɛ-caprolactone) matrix for film-based stent

Drug-loaded biodegradable films as a principal part of film-based stent were investigated for controlled drug delivery systems. In this study, solid dispersion technique, a pretreatment method of paclitaxel (PTX), was applied to prepare the PTX-loaded poly(?-caprolactone) (PCL) films. Drug dissolution rates and characteristics of the poly(vinyl pyrrolidone) (PVP)/PTX solid dispersions (SDs) and physical mixtures (PMs) were investigated to show that the PVP/PTX SDs were successfully prepared before being incorporated in biodegradable films. Afterwards, the effect of the application of SDs on improving drug release behavior, weightlessness, crystalline states, and surface and internal morphologies of the films were studied. It was found that, the films with SDs showed a higher drug release rate than the films with PMs or pure PTX. In addition, the content of PVP in the SDs also had impact on drug release behavior: the more PVP in SDs, the faster the drug was released. According to the drug release test and weightlessness study, the possible drug release mechanism was put forward for the films with SDs. The application of solid dispersion technique showed a remarkable effect on improving drug release behavior for film-based biodegradable stent drug delivery systems.     

Characterization of the self assembly of methoxy poly(ethylene oxide)-block-poly(α-benzyl carboxylate-ε-caprolactone) for the solubilization and in vivo delivery of valspodar

The aim of this study was to characterize the nanostructures formed from assembly of poly(ethylene oxide)-bpoly( α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL) in water, determine the effect of weight fraction of the hydrophilic block( fEO) on their morphology, and to investigate their potential for solubilization and delivery of P-glycoprotein (P-gp) inhibitor, valspodar. Three PEO-b-PBCL block copolymers having fEO ranging from 0.18-0.40 were synthesized. Assembly of PEO-b-PBCL was triggered through a co-solvent evaporation method. The average critical aggregation concentration (CAC) for PEO114-b-PBCL??, PEO???-b-PBCL??, and PEO???-b-PBCL?? was found to be 62, 41, and 23 nM, respectively. A lower rigidity of the hydrophobic domain in nanostructures formed from the assembly of PEO???-b- PBCL?? and PEO???-b-PBCL?? in comparison to PEO???-b-PBCL?? was observed. The morphology of the assembled structures was characterized by transmission electron microscopy (TEM). The TEM images of PEO???-b-PBCL?? (fEO = 0.40) showed the formation of spherical micelles with high polydispersity, whereas the assembly of PEO???-b-PBCL?? (fEO = 0.25) and PEO???-b-PBCL95 (fEO = 0.18) resulted in a mixed population of spherical micelles and vesicles. Valspodar achieved high loading in all the three PEO-b-PBCL nanocarriers reaching aqueous solubility of nearly 2 mg/mL. The morphology of PEO-b-PBCL carrier did not seem to influence the pharmacokinetics of the encapsulated valspodar in rats following intravenous administration. In conclusion, the results show a potential for PEO-b-PBCL nanocarriers as efficient solubilizing agents for delivery of valspodar.     

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.     

Functionalized (poly(ɛ-caprolactone))₂-poly(ethylene glycol) nanoparticles with grafting nicotinic acid as drug carriers

Nicotinic acid was grafted on (poly(?-caprolactone))₂-poly(ethylene glycol) copolymers that were used for the preparation of nanoparticles with the objectives to monitor particle size and to optimize the drug loading capacity as well as the release profile of the particles. Increasing amounts of grafting nicotinic acid increased the particle size as a result of an enhanced hydrophobicity of the copolymer. Ibuprofen and indomethacin with two different molecular characteristics were selected as model drugs to be bound to the nanoparticles. The presence of grafting nicotinic acid enhanced the loading capacity for both drugs compared to the nanoparticles without nicotinic acid. However, no correlation between amount of grafting nicotinic acid and loading capacity was observed. The release characteristic of both drugs was fitted to the Higuchi model indicating Fickian diffusion. The release characteristic of indomethacin mainly depended on the crystalline property of the copolymer whereas that of ibuprofen was additionally influenced by the hydrogen bonding between drug and grafted copolymer.