Drug Loading Behavior Research Articles

Effect of molecular architecture on micellization, drug loading and releasing of multi-armed poly(ethylene glycol)-b-poly(ε-caprolactone) star polymers

This study investigated the effect of molecular architecture of amphiphilic star polymers on micelle formation and drug loading and releasing. For this, multi-armed star block copolymers having poly(ethylene glycol) as a hydrophilic block and poly(e-caprolactone) as a hydrophobic block were synthesized by using a divergent synthetic method consisting of a coupling reaction and a ring opening polymerization. The molecular weight and molecular weight distribution of the block copolymers were characterized by 1H NMR and GPC measurements. Dynamic light scattering and fluorescence spectroscopic analysis were employed to observe micellization, drug loading, and drug release behaviors. We have figured out that the number of arms is a critical factor that changes critical micelle concentration as well as drug loading and releasing behaviors; increase in the number of arms not only led to lowering the critical micelle concentration and drug release rate but also increased the micelle size and drug loading efficiency.

Preparation and characterization of PLGA microspheres by the electrospraying method for delivering simvastatin for bone regeneration

Microparticles formulated from poly (D,L-lactic-co-glycolide) (PLGA), a biodegradable polymer, have been investigated extensively as a drug delivery system. In this study, solid tiny PLGA microspheres were fabricated using the electrospraying method. PLGA polymer was dissolved in dichloromethane (DCM), and the solution was electrosprayed. The electrospraying conditions were adjusted so that the stream ejected from the needle was divided into spheres instead of continuous fibers or irregular-shaped particles. Several experiments were carried out using the PLGA-DCM source solution with different amounts of simvastatin (SIM), a drug that enhances bone regeneration, to understand this drug delivery system. The surface morphology and microstructure of the microspheres formed were characterized by scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, and differential scanning calorimetry. The in vitro experiments on drug loading and drug release behavior of the microspheres suggested a drug encapsulation efficacy >90%. The drug was continuously released from the microspheres for >3 weeks. Other experiments, such as MTT, cell attachment and proliferation and reverse transcription-polymerase chain reaction showed good biocompatibility of the electrosprayed PLGA microspheres, which increased in the presence of SIM. Thus, electrosprayed PLGA microspheres have potential as a drug delivery system and application in bone tissue engineering.

Generation of porous poly-l-lactide microspheres by emulsion-combined precipitation with a compressed CO2 antisolvent process.

An emulsion-combined precipitation of compressed CO2 antisolvent (PCA) process was used to fabricate porous poly-l-lactide (PLLA) microspheres (PLLA PMs). A 24 full factorial experiment was performed to optimize the operating process and analyze the effect of the factors on the size and morphology of the PLLA PMs. An investigation of their in vitro cytotoxicity was also performed. Taking methotrexate (MTX) as a drug model, MTX-loaded PLLA PMs (MTX-PLLA PMs) were fabricated by the optimized process. Drug loading behaviors and in vitro inhibitory activity against A549 lung cancer cells were also evaluated. The resulting PLLA PMs and MTX-PLLA PMs both exhibited a porous and uneven morphology, with a density less than 0.4 g cm-3, a geometric mean diameter (Dg) of 10-25 μm, an aerodynamic diameter (Da) less than 4.7 μm, a fine particle fraction (FPF) of 58-62%, and a porosity of 79-85%, meeting the requirements for pulmonary drug delivery. Various characterizations revealed that no chemical change occurred in the PLLA, while a slight shift in the molecular structure of MTX was observed after the process, as well as a change in its physical state from crystalline to amorphous. No obvious cytotoxicity was detected for the PLLA PMs, and the MTX-PLLA PMs displayed a sustained release profile with an encapsulation efficiency (EE) of 81.6%. The fluorescent MTX-PLLA PMs also revealed that most of the drug was homogeneously distributed inside the matrix. An in vitro antitumor assay indicated that the MTX-PLLA PMs possessed a sustained and improved inhibitory activity compared with the raw MTX. This study demonstrates that the emulsion-combined PCA process has potential for developing a promising inhalable carrier for pulmonary drug delivery.

Synthesis of 4-Acryloylmorpholine-based Hydrogels and Investigation of their Drug Release Behaviors

In this study, hydrogels based on an amphiphilic, water soluble, bisubstituted and biocompatible acrylamide derivative, namely 4-acryloylmorpholine (4-AcM), were prepared. 4-AcM based hydrogels with different compositions were synthesized by photopolymerization from the mixtures of poly(ethylene glycol) diacrylate (PEG-DA) and poly(2-hydroxy ethyl methacrylate) (HEMA), and characterized by Fourier transform infrared spectroscopy (FTIR). Gel percentage and equilibrium swelling ratios were determined. Images obtained by scanning electron microscopy (SEM) confirmed porous structure of the hydrogels. Ciprofloxacin.HCl was chosen as a model drug in order to understand the drug loading and release behaviors of the hydrogels. As 4-AcM content increased, higher drug release was observed. On the other hand, the increase in crosslinking density due to PEG-DA content resulted in the swelling decrease of the hydrogel and reduced the diffusion of the drug.

In situ generation of sodium alginate/hydroxyapatite/halloysite nanotubes nanocomposite hydrogel beads as drug-controlled release matrices.

Diclofenac sodium-loaded sodium alginate/hydroxyapatite/halloysite nanotubes (SA/HA/HNTs-DS) nanocomposite hydrogel beads were prepared by the in situ generation of HA nanoparticles during the sol-gel transition of the SA/HNTs suspension. The nanocomposite beads were characterized by FT-IR spectroscopy, thermogravimetric analysis and field emission scanning electron microscopy, etc. Factors, e.g., the weight ratio of HNTs to SA (mHNTs/mSA), the weight ratio of (NH4)2HPO4 to SA (m(NH4)2HPO4 /mSA), and the concentration of SA, which influenced the entrapment efficiency (EE) and release of DS, were investigated. The EE was enhanced from 62.85 ± 0.29% to 74.63 ± 1.65%, and the burst release of DS was overcome by introducing appropriate amounts of HA and HNTs. An almost constant rate release of DS is achieved when mHNTs/mSA = 0.3 and m(NH4)2HPO4 /mSA = 0.1. The release rate of DS from the SA/HA/HNTs-DS beads was 9.19 mg g-1 h-1. The release of DS is controlled by Case-II transport. The tubular structure of the HNTs and the in situ-formed HA nanoparticles can restrict movability of the SA polymer chains, which is the main reason for the improved drug loading and release behavior.

Hollow nanosphere fabricated from β-cyclodextrin-grafted α,β-poly(aspartic acid) as the carrier of camptothecin

This research is aimed to develop a kind of hollow nanosphere based on β-cyclodextrin-grafted α, β-poly(aspartic acid) (β-CD-graft-PAsp) as drug carrier to enhance the stability of camptothecin (CPT) in aqueous media. Firstly, mono(6-(2-aminoethyl) amino-6-deoxy)-β-cyclodextrin (β-CDen) was synthesized by a substitution reaction between mono-6-deoxy-6-(p-tolylsulfonyl)-β-cyclodextrin (6-OTs-β-CD) and ethylenediamine; and then, the five-member rings in poly(l-succinimide) (PSI) were successively opened by β-CDen to obtain β-CD-graft-PAsp. The synthesized β-CD-graft-PAsp was found to form the unique hollow nanosphere with the internal hole of about 17nm and many β-CD cavities of 0.7nm interspersed on the shell. The drug-loading behavior of the hollow nanosphere was also evaluated by using CPT as guest molecule of β-CD. It was worth of note that the β-CD-graft-PAsp hollow nanosphere as carrier enhanced the stability of CPT in aqueous media, and the CPT from the β-CD-graft-PAsp hollow nanosphere displayed a sustained release profile and hence resulted in the essential decrease of cytotoxicity to L929 cell line. Furthermore, almost no cytotoxicity of the β-CD-graft-PAsp is desirable for the application of drug carrier. As a result, the β-CD-graft-PAsp hollow nanosphere showed a great potential as the carrier of CPT.

Enhancement of Solubility and Dissolution Characteristics of Ibuprofen by Solid Dispersion Technique

In this study solid dispersions (SDs) of ibuprofen were prepared by melt dispersion technique using macrogol 4000 and macrogol 6000 as carrier. Physical mixtures (PMs) of ibuprofen were also prepared with the same carrier and in the same drug-carrier ratio (1:0.5, 1:1 and 1:1.5) to compare the dissolution profile. The solid dispersions and physical mixtures were investigated for drug loading, saturation solubility and dissolution behavior. Saturation solubility study was carried out in phosphate buffer (pH 7.2), 0.1 N HCl solution and distilled water. Solid dispersions were found effective to enhance the solubility of ibuprofen significantly in all the media. Dissolution test was carried out in two different media, phosphate buffer (pH 7.2) and 0.1 N HCl. Solid dispersion containing macrogol 6000 at the ratio of 1:1.5 (drug: carrier) showed faster and higher drug release and was found to be most effective among all the solid dispersions. Drug carrier interactions were studied by comparing Fourier Transform Infrared Spectroscopy (FT-IR) of solid dispersions with pure drug which revealed that the SDs were stable. So, solid dispersion may be an effective technique to enhance dissolution rate of ibuprofen. DOI: http://dx.doi.org/10.3329/dujps.v11i1.12480 Dhaka Univ. J. Pharm. Sci. 11(1): 1-6, 2012 (June)

Development and optimization of thiolated dendrimer as a viable mucoadhesive excipient for the controlled drug delivery: An acyclovir model formulation

In the present study we report the development of novel thiolated dendrimers for mucoadhesive drug delivery. The thiolated dendrimers were synthesized by conjugating PAMAM dendrimer (G3.5)with cysteamine at two different molar ratios, i.e. 1:30 (DCys1) and 1:60 (DCys2). The thiolated dendrimers were further encapsulated with acyclovir (DCys1Ac and DCys2Ac) and the conjugates were characterized for thiol content, drug loading, drug release, and mucoadhesive behavior. The thiolated dendrimer conjugates showed thiol content of 10.56±0.34 and 68.21±1.84 μM/mg of the conjugate for DCys1 and DCys2, respectively. The acyclovir loading was observed to be highest in dendrimer drug conjugate (DAc) compared to other DCys1Ac and DCys2Ac conjugates. The thiolated dendrimers showed sustained release of acyclovir and showed higher mucoadhesion. The in vitro mucoadhesive activity of DCys2Ac was 1.53 and 2.89 fold higher mucoadhesion compared to DCys1Ac and DAc, respectively. These results demonstrated the usefulness of thiolated dendrimers as a mucoadhesive carrier and represent a novel platform for drug delivery. From the Clinical EditorThis study demonstrates the utility of thiolated dendrimers as mucoadhesive carriers as reported in an acyclovir delivery model system.

Poly(acrylic acid)‐Modified Fe3O4 Microspheres for Magnetic‐Targeted and pH‐Triggered Anticancer Drug Delivery

Monodisperse poly(acrylic acid)-modified Fe(3)O(4) (PAA@Fe(3)O(4)) hybrid microspheres with dual responses (magnetic field and pH) were successfully fabricated. The PAA polymer was encapsulated into the inner cavity of Fe(3)O(4) hollow spheres by a vacuum-casting route and photo-initiated polymerization. TEM images show that the samples consist of monodisperse porous spheres with a diameter around 200 nm. The Fe(3)O(4) spheres, after modification with the PAA polymer, still possess enough space to hold guest molecules. We selected doxorubicin (DOX) as a model drug to investigate the drug loading and release behavior of as-prepared composites. The release of DOX molecules was strongly dependent on the pH value due to the unique property of PAA. The HeLa cell-uptake process of DOX-loaded PAA@Fe(3)O(4) was observed by confocal laser scanning microscopy (CLSM). After being incubated with HeLa cells under magnet magnetically guided conditions, the cytotoxtic effects of DOX-loaded PAA@Fe(3)O(4) increased. These results indicate that pH-responsive magnetic PAA@Fe(3)O(4) spheres have the potential to be used as anticancer drug carriers.

Microfluidics assisted fabrication of microspheres by poly(2–hydroxyethyl methacrylate)-block-poly(l-histidine) hybrid materials and their utilization as potential drug encapsulants

A new series of synthetic polymer bioconjugate hybrid materials consisting of poly(2-hydroxyethyl meth- acrylate)(p(HEMA))as a synthetic polymer block and poly(L-histidine) (p(His)) as a polypeptide block were syn- thesized by combining atom transfer radical polymerization of HEMA with ring opening polymerization of benzyl- N-carboxy-L-histidine anhydride. The resulting biocompat- ible p(HEMA)25-b-p(His)n (n = 15, 25, 35, and 45) hybrid polymers were investigated for their use as pH-sensitive drug delivery system. Highly uniform microspheres were fabricated by using the microfluidics assisted self-assembly of these block polymers and utilized them as carriers for a chemotherapeutic agent doxorubicin and a beta-lactam antibiotic ampicillin for the evaluation of the drug-loading and release behaviors according to pH, demonstrating the release is sensitive to pH. The capability of the new p(HEMA)-b-p(His) hybrid materials to self-assemble in microenvironments and to effectively encapsulate drug molecules serves as suitable carriers for the delivery of drug molecules with varying physiochemical properties.

Preparation and evaluation of a sustained-release suspension containing theophylline microcapsules

A great effort has been devoted to the preparation of sustained-release formulations of theophylline to prevent large fluctuations of serum concentration and increasing the therapeutic efficacy followed by patient compliance. In the present study, microcapsules of theophylline with ethyl cellulose (EC) were prepared by emulsion-solvent evaporation method in different polymer to drug ratios. Size, morphology, drug loading and release behavior of microcapsules were also studied. Microcapsules were then formulated into suspensions to provide an oral liquid dosage form for drug and resulting suspensions were examined for stability and release characteristics in various storage times. Results showed that microcapsules prepared in drug to polymer ratio 1:1.4 by emulsifying polymer solution in liquid paraffin presented the sustained-release properties which met the United States Pharmacopeia (USP) (2007) requirements (t50% and t80% of these microparticles were 150 and 360 min, respectively). The suspensions prepared by these microcapsules were also stable in the study period and their release profiles were consistent to the original microcapsules. The results allow for the conclusion that the formulated suspension can be used as a sustained-release formulation for theophylline in treatment of obstructive pulmonary disorders. Key words: Theophylline, microencapsulation, suspension, sustained-release, ethyl cellulose.

COMPARATIVE IN VITRO DISSOLUTION STUDY OF SPIRONOLACTONE FROM BINARY AND TERTIARY SOLID DISPERSION: MODEL DEPENDANT AND INDEPENDENT APPROACHES

 Abstract: In this study solid dispersions (SDs) of spironolactone were prepared by solvent evaporation technique using poloxomer 407,  kollicoat IR, kollidon VA 64 and PEG 6000 as carrier. The solid dispersions were investigated for drug loading and dissolution behavior. Solid dispersions were found effective to enhance the solubility of spironolactone significantly in the dissolution media. Dissolution test was carried out purified water. Solid dispersion containing kollidon VA 64 at the ratio of 1:20, showed faster and higher drug release and was found most effective among all the solid dispersions. Drug carrier interactions were studied by comparing Fourier Transformed Infrared Spectroscopy (FT-IR) spectra of solid dispersions with pure drug and the SDs were found stable. Dissolution results of all the formulations were compared by using difference factor (f1), similarity factor (f2), dissolution efficiency (%DE) and multiple comparison Bonferroni test. No significant difference was found among the binary SDs containing 1:5 carrier, on the other hand all the ternary SDs were also found similar. So, solid dispersion technique may be an effective technique to enhance dissolution rate of spironolactone.

Preparation and in vitro characterization of dexamethasone-loaded poly(d,l-lactic acid) microspheres embedded in poly(ethylene glycol)–poly(ɛ-caprolactone)–poly(ethylene glycol) hydrogel for orthopedic tissue engineering

The corium is decreased to about half of its thickness in skin defects and wrinkles due to gravity and environment. In this study, dexamethasone/poly(d,l-lactic acid) (Mn = 160,000) microspheres were incorporated into poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (Mn = 3300) hydrogel to prepare an injectable hydrogel composite. The composite was designed to increase the thickness of the corium. Dexamethasone/poly(d,l-lactic acid) microspheres were prepared by oil-in-water emulsion/solvent evaporation technique. The properties of microspheres were investigated by size distribution measurement, scanning electron microscope and x-ray diffraction. Drug loading, encapsulation efficiency, and drug delivery behavior of microspheres were also studied in detail. Cell adhesion of microspheres was investigated by NIH3T3 cell invitro. The properties of hydrogel composite were investigated by scanning electron microscope, rheological measurements and methyl thiazolyl tetrazolium assay. Drug release from composite was determined by HPLC-UV analysis. These results suggested that poly(d,l-lactic acid) microspheres encapsulating dexamethasone embedded in poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) hydrogel might have prospective application in orthopedic tissue engineering field.

Facile method for synthesis of hollow porous magnetic microspheres with controllable structure

Hollow porous magnetic microspheres with strong magnetization and controllable structure were prepared via a facile electrostatic self-assembly of the positively charged Fe3O4 nanoparticles onto the surface of the negatively charged poly(N,N′-methylenebisacrylamide-co-methacrylic acid) (P(MBAAm-co-MAA)) microspheres with subsequent removal of the polymer core through calcination at high temperature. The shell thickness was facilely tuned through the ratio between Fe3O4 and polymer, and the void space was conveniently changed through the size of polymer microspheres. The hollow magnetic microspheres possessed high saturation magnetization value (51.38emu/g) and porous structure with high specific surface area (108.04m2/g). Based on these properties, the drug loading and release behaviors were investigated, which indicated that the hollow magnetic microspheres exhibited a controlled release process.

Synthesis and characterization of novel dual-responsive nanogels and their application as drug delivery systems

In this study, a temperature/pH dual-response nanogel based on NIPAm, MAA, and PEGMA was synthesized via emulsion polymerization and characterized by (1)H-NMR, FT-IR, TEM and DLS. By introducing a novel initiator, through which PEG-AIBN-PEG was synthesized, it was revealed that the PEG segments from PEG-AIBN-PEG with a dosage of initiator had a significant influence over the macro-state and stability of the nanogels. In order to optimize the feeding prescription for better application as a drug delivery system, the effect of the co-monomer contents on the response to stimuli (temperature and pH value) and cytotoxicity of the nanogels has been studied in detail. The results demonstrated that the responsiveness, reversibility and volume phase transition critical value of the nanogels could be controlled by adjusting the feeding ratio of the co-monomers in the synthesis process. MTT assay results revealed that nanogels with appropriate compositions showed good biocompatibility and relatively low toxicity. Most importantly, by studying the drug loading behavior, it was found that the dimensions of the drug molecules had a considerable influence on the drug loading efficiency and loading capacity of the nanogels, and that the mechanism by which drug molecule sizes influence the drug loading behavior of nanogels needs further investigation. The results indicated that such PNMP nanogels might have potential applications in drug delivery and other medical applications, but that the drug loading mechanism must be further developed.

Polymeric micelles based on poly(ethylene glycol) block poly(racemic amino acids) hybrid polypeptides: conformation-facilitated drug-loading behavior and potential application as effective anticancer drug carriers

In this work, racemic hybrid polypeptides poly(ethylene glycol) (PEG)-b-poly(racemic-leucine) (PRL) copolymers with different leucine residues have been synthesized and characterized. Using docetaxel as a model molecule, the high drug-loaded spherical micelles based on PEG-PRL were prepared successfully using dialysis, with a tunable particle size from 170 nm to 250 nm obtained by changing the length of the hydrophobic blocks. Facilitated drug-loading behavior (higher drug-loading ability and easier drug-loading process) of PEG-PRL compared with their corresponding levo forms (PEG-b-poly[levo leucine]) was observed and clarified for the first time. With this facilitation, the highest drug-loading content and efficiency of PEG-PRL micelles can achieve 11.2% ± 0.4% and 67.2% ± 2.4%, respectively. All drug-loaded PEG-PRL micelles exhibit a similar release behavior with a sustained release up to 72 hours. The PEG-PRL was shown to be nontoxic against MCF-7 and human umbilical vein endothelial cells up to a concentration of 100 μg/mL, displaying a good biocompatibility. Also, the docetaxel-loaded PEG-PRL micelles were more toxic than the free drug against MCF-7 human breast cancer cells – both dose and time dependent. Therefore, these high docetaxel-loaded micelles based on racemic hybrid polypeptides appear to be a novel promising nanomedicine for anticancer therapy.

Development of an amorphous mesoporous TiO2 nanosphere as a novel carrier for poorly water-soluble drugs: Effect of different crystal forms of TiO2 carriers on drug loading and release behaviors

Cotton-like amorphous mesoporous titania (APMT) nanoparticles with 3-D netlike pores were synthesized by a simple and reproducible method and the potential of APMT as a carrier for poorly water-soluble drugs was explored. In order to study the effect of different crystal forms of titania on drug loading and release behaviors, a novel anatase mesoporous titania (ATMT) was also prepared through a facile method using pluronic F127 as a template and titanium(IV) isopropoxide (TIP) as a titania source. The model drug carvedilol (CAR) was effectively loaded into the pores of APMT and ATMT through solvent deposition method, according to results of differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). In compared with ATMT, APMT showed a more rapid release profile, which may be attribute to the netlike pores, small pore size (2–3nm) as well as absorbed water and hydrate water on the surface, based on results of X-ray diffraction (XRD), N2 adsorption/desorption, SEM/TEM and in vitro dissolution test. Definitely, the results confirmed that the drug loading and release behaviors were heavily dependent on the crystal forms of the carriers, which will provide a new thread for formulation of poorly water-soluble drugs.

Preparation and Drug Release Properties of IBU-Loaded Mesoporous Calcium Silicate Hydrate (CSH) Spheres

The novel kind flowerlike mesoporous spheres of calcium silicate hydrate (CaO•SiO2•H2O, CSH) have been synthesized by co-precipitation method on based with water/alcohol/calvital/ tetraethyl orthosilicate (TEOS) system. The synthesized CSH were applied as a carrier to study the loaded behaviors of ibuprofen(IBU),was used to investigate the drug loading behavior of the CSH for different times has been also discussed. The drug loading capacities(DLCs) of CSH loaded for 12h has reached 116.78wt.%. The structural, morphological and textural properties were investigated by SEM, FTIR, TG and BET. The results show that it would be a good candidate as drug carrier for bone repair.

Preparation and characterization of temperature-responsive and magnetic nanomicelles

One type of the temperature-responsive and magnetic nanomicelles was synthesized based on SPIONs (superparamagnetic iron oxide nanoparticles) and the biocompatible polymer-Pluronic F127 or its copolymer with poly(DL-lactic acid) (F127–PLA) via a facile chemical conjugation method. The magnetic nanomicelles were characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), thermogravimetric analysis (TGA), a vibrating sample magnetometer (VSM), dynamic light scattering measurements (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The varying volume shrinkage of the magnetic nanomicelles was detected when increasing the temperature from 15 to 45 °C. Doxorubicin hydrochloride (DOX·HCl) was selected as a model anticancer drug to investigate the drug loading and release behavior in the buffer solutions with different pH values and in an alternating magnetic field (MF). The Alamar blue assay was performed to evaluate the biocompatibility of the micelles and the antiproliferative effect of the drug-loaded micelles. The results displayed that the magnetic micelles were safe carriers and the DOX·HCl-loaded micelles were equally effective as the free drug for suppressing the growth of tumor cells. The blood compatibility studies showed few effects on coagulation and hemolysis. Therefore, the magnetic micelles possess many great potential applications in the field of nanomedicine.

Ordered mesoporous carbons for ibuprofen drug loading and release behavior

Ibuprofen (IBU) was selected as model drug and loaded onto ordered mesoporous carbons (OMCs). Effect of the OMCs structures on IBU drug loading and release was studied for the first time. The carbon materials before and after IBU loading were characterized by N 2 sorption analysis, small angle X-ray diffraction (XRD) and transmission electron microscopy (TEM). The results showed that the loading of IBU had not greatly changed the basic ordered pore structure of the OMCs. The IBU adsorption process followed the Langmuir adsorption and the adsorbed IBU amount was mainly a function of the specific surface area and pore volume. The two-step release process of a first fast release and then a slower release was observed. The release behavior of IBU was well correlated with time using a simple hyperbolic equation. The pore size was a crucial factor for the release rate of IBU, which increased with the increase of pore size.