International Journal of Pharmaceutics (v.394, #1-2)
Editorial Board (iii).
Foams for pharmaceutical and cosmetic application by A. Arzhavitina; H. Steckel (1-17).
Foaming of cleaning agents in the household is an effect which is not connected with the quality of cleaning process. Foam development of some cosmetic formulations such as hair mousse or shaving foam has its functionality. Foam formation during application of a foam bath or shampoo is only a cosmetic attribute. In the pharmacy, foams represent new vehicles for drug delivery. The European Pharmacopoeia comprises a monograph called “Medicated Foams” and the interest for the development of these alternative vehicles is steadily growing. Depending on the way of pharmaceutical application we can define between rectal, vaginal and topical foams. Foams for dermal drug delivery have some advantages compared to the traditional vehicles for treatment of topical disorders such as ointment, creams, lotions, gels or solutions. Vaginal and rectal foam vehicles also feature some application benefits compared to the standard vehicles such as suppositories, creams and ointments. There are only a few foam formulations commercially available so far. Moreover, only few publications describing these vehicles have appeared in the recent years, predominantly patents. It is the intention of this article to review available literature, to summarize recent development and to highlight the potential of foam vehicles.
Keywords: Dermal foams; Rectal foams; Vaginal foams; Foam stability; Pressurized aerosol foam;
Quantitation of a polymorphic mixture of an active pharmaceutical ingredient with solid state 13C CPMAS NMR spectroscopy by Tommi Virtanen; Sirkka L. Maunu (18-25).
Active pharmaceutical ingredients (API) often crystallise in several forms with significant differences in their physical properties. In pharmaceutical applications it is very important to be able to identify these polymorphs during drug manufacturing and storaging, also quantitative information about polymorphs is often required. Solid state 13C cross-polarisation (CP), magic angle spinning (MAS), nuclear magnetic resonance (NMR) spectroscopy was utilised in studying polymorphisity of an API with two polymorphic forms. Quantitative information was obtained from polymorphic mixtures, and a formulated product was also studied in order to determine the possibility of distinguishing between the two polymorphs in a low-dose formulation. Quantitative data was obtained using two methods: integration of signals from the dipolar dephased spectra, and a chemometric method known as Direct Exponential Curve Resolution Algorithm (DECRA). We concluded that the two polymorphs are easily identifiable based on their spectral differences. Quantitative results showed reasonable accuracy, and while identification of the polymorph present in formulation was not possible, traces of the API are detectable in as low dosage as 0.7% by weight using solid state NMR methods.
Keywords: Solid state NMR; Polymorphism; Quantitation; DECRA;
Synthesis, characterization and in vitro evaluation of a bone targeting delivery system for salmon Calcitonin by Krishna Hari Bhandari; Madhuri Newa; Hasan Uludag; Michael R. Doschak (26-34).
Synthetic salmon Calcitonin (sCT) is currently used to treat and manage conditions associated with low bone mass, and elicits its antiresorptive effect by acting upon Calcitonin receptors (CTRs) located on bone-resorbing osteoclast cells. However, CTRs are also widely distributed in many non-skeletal tissues (such as kidney, brain, and lung), and the competitive uptake of available sCT amongst such CTRs likely reduces sCT availability for bone resident osteoclast cells, particularly if the drug is administered systemically and not specifically targeted to bone. Hence, the objective of this study was to synthesize and characterize a bisphosphonate (BP)-mediated bone targeting delivery system for sCT and to determine whether the bioactivity of sCT was retained after BP conjugation. BP–sCT conjugates were synthesized by initially reacting sCT with sulfosuccinimidyl-4-[N-maleimidomethyl]cyclohexane-1-carboxylate (sulfo-SMCC) in dimethyl formamide in the presence of triethylamine (TEA) at room temperature. Thiolated (Thiol)-BP was then reacted with the sCT–sulfo-SMCC conjugates to generate sCT–BP conjugates, which were purified by dialysis and assayed using the micro-BCA protein assay. Non-BP containing control sCT–Cysteine conjugates were also synthesized using the same procedure. Reactions were monitored and characterized using matrix-assisted laser desorption ionization time-of-flight mass spectrometer (MALDI-TOF) analysis and Tris–Tricine SDS-PAGE. Conjugates were evaluated for in vitro bone mineral affinity using a hydroxyapatite binding test, for bone mineral specificity using different calcium salt binding affinity assays, and for continued sCT bioactivity after conjugation using an intracellular cAMP stimulation in human T47D breast cancer cells. Our results confirmed that BP-conjugated sCT exhibited significantly greater affinity and specificity for bone mineral over unmodified sCT, and that sCT–BP conjugates retained strong CT bioactivity after conjugation. Our conjugation strategy holds the promise of facilitating the delivery of sCT preferentially to skeletal bony tissues, thereby increasing its local concentration to bone surfaces. This peptide hormone–bisphosphonate drug system represents a new class of antiresorptive drug that has not previously been attempted, nor has a bone targeting formulation of sCT been reported.
Keywords: Calcitonin; Bisphosphonate; Bone targeting; Drug delivery system; Osteoporosis; Paget's disease; Bone cancer; Rheumatoid arthritis; Osteoarthritis;
In vitro identification of targeting ligands of human M cells by phage display by V. Fievez; L. Plapied; C. Plaideau; D. Legendre; A. des Rieux; V. Pourcelle; H. Freichels; C. Jérôme; J. Marchand; V. Préat; Y.J. Schneider (35-42).
To improve transport of vaccine-loaded nanoparticles, the phage display technology was used to identify novel lead peptides targeting human M cells. Using an in vitro model of the human follicle-associated epithelium (FAE) which contains both Caco-2 and M cells, a T7 phage display library was screened for its ability either to bind the apical cell surface of or to undergo transcytosis across Caco-2 cells or FAE. The selection for transcytosis across both enterocytes and FAE identified three different peptide sequences (CTGKSC, PAVLG and LRVG) with high frequency. CTGKSC and LRVG sequences enhanced phage transport across M-like cells. When polymeric nanoparticles were grafted with the sequences CTGKSC and LRVG, their transport by FAE was significantly enhanced. These peptides could therefore be used to enhance the transport of vaccine-loaded nanoparticles across the intestinal mucosal barrier.
Keywords: Oral delivery; Targeting; M cells; Caco-2 cells; Phage display; Nanoparticles;
Aggregation behavior of self-assembling polylactide/poly(ethylene glycol) micelles for sustained drug delivery by Liu Yang; Xu Qi; Pei Liu; Abdelslam El Ghzaoui; Suming Li (43-49).
A series of diblock copolymers were synthesized by ring-opening polymerization of l- or d-lactide in the presence of monomethoxy poly(ethylene glycol) (mPEG) with molar masses of 2000 and 5000. The aggregation behavior of the resulting water soluble PLA/PEG diblock copolymers in aqueous medium was studied with dynamic and static light scattering (DLS and SLS), in combination with aqueous gel permeation chromatography (GPC). The average hydrodynamic radius (R h) of l-PLA/PEG and d-PLA/PEG mixed micelles is lower than that of l-PLA/PEG single micelles due to the stereocomplexation effect between l-PLA and d-PLA blocks. It is also confirmed that the micelle size increases with increasing temperature and hydrophobic block length, but decreases after salt addition. Aqueous GPC and SLS were used to evaluate the molecular weight (M w) and aggregation number (N agg) of the micelles. Mixed micelles present lower N agg than single copolymer micelles due to stereocomplexation. N agg decreases with increasing hydrophobic block length, and decreases upon addition of NaCl, in agreement with a more compact structure. In contrast, N agg increases with elevating temperature. The average radius of gyration (R g) and R g/R h ratio data show that both increase with increasing temperature, suggesting that micelles exhibit a compact hard-sphere structure at 15 °C and a swollen structure at 35 °C. As the temperature increases from 15 °C to 35 °C, the second virial coefficient (A 2) of PLA/PEG copolymers turns from negative to positive, which means that water changes from poor solvent to good solvent. The fact that the average density (ρ) of PLA/PEG micelles decreases with increasing temperature confirms that micelles exhibit a looser structure at higher temperatures due to water swelling effect. The higher ρ value of mixed micelles as compared to single micelles also confirms a more compact structure of the former. In addition, due to the much higher N agg and lower R h, PLA/PEG2000 micelles present higher ρ value than PLA/PEG5000 ones.
Keywords: Polylactide; Stereocomplexation; Poly(ethylene glycol); Micelle; Aggregation number; Second virial coefficient;
Improving aerosolization of drug powders by reducing powder intrinsic cohesion via a mechanical dry coating approach by Qi Tony Zhou; Li Qu; Ian Larson; Peter J. Stewart; David A.V. Morton (50-59).
The aim of this study was to investigate the effect of coating on the aerosolization of three model micronized powders. Three model powder materials (salbutamol sulphate, salmeterol xinafoate, triamcinolone acetonide) were chosen not only for their different chemical properties but also for their different physical properties such as shape and size distribution. Each powder was coated with 5% (w/w) magnesium stearate using two different dry mechanofusion approaches. After mechanofusion, both poured and tapped densities for all three model drug powders significantly increased. There were significant improvements in aerosolization behavior from an inhaler device for all model powders after mechanofusion. Such improvements in aerosolization were attributed to the reduction in agglomerate strength caused by decreasing powder intrinsic cohesion via surface modification. The work also indicated that the effect of the coating was dependant on the initial particle properties.
Keywords: Dry powder inhalers; Aerosolization; Powder cohesion; Mechanical coating; Mechanofusion;
Passive asymmetric transport of hesperetin across isolated rabbit cornea by Ramesh Srirangam; Soumyajit Majumdar (60-67).
Hesperetin, an aglycone of the flavanone hesperidin, is a potential candidate for the treatment of diabetic retinopathy and macular edema. The purpose of this investigation was to determine solubility, stability and in vitro permeability characteristics of hesperetin across excised rabbit corneas. Aqueous and pH dependent solubility was determined using standard shake flask method. Solution stability was evaluated as a function of pH (1.2–9) and temperature (25 and 40 °C). Permeability of hesperetin was determined across the isolated rabbit cornea utilizing a side-bi-side diffusion apparatus, in the apical to basolateral (A–B) and basolateral to apical (B–A) directions. Hesperetin displayed asymmetrical transcorneal transport with a 2.3-fold higher apparent permeability in the B–A direction compared to the A–B direction. The transport process was observed to be pH dependent. Surprisingly, however, the involvement of efflux transporters or proton-coupled carrier-systems was not evident in this asymmetric transcorneal diffusion process. The passive and pH dependent corneal transport of hesperetin could probably be attributable to corneal ultrastructure, physicochemical characteristics of hesperetin and the role of transport buffer components.
Keywords: Hesperetin; Hesperidin; Eye; Permeability; Physicochemical; Transcorneal; Asymmetric transport; Transporters; Stability;
Inhibition of crystallization in drug-in-adhesive-type transdermal patches by Piyush Jain; Ajay K. Banga (68-74).
In this study the ability of various additives to inhibit crystallization of two model drugs, captopril and levonorgestrel, in acrylate and silicone adhesives was investigated. Among the various additives tested, PVP was found to be the most effective in inhibiting the crystallization of both drugs. Incorporation of PVP in patches (PVP stabilized patches) allowed incorporation of both drugs in amounts higher than their respective saturation solubility in pure adhesives (saturated patches). Skin permeation profiles of the drugs from the patches across hairless rat skin were obtained using Franz diffusion cells. For the hydrophilic drug captopril the skin flux over the first 24 h was the same for the saturated and PVP stabilized patches, but after 24 h the PVP stabilized patches produced higher skin flux values. However this may be because the saturated patch was depleted of the drug after 24 h. It is not clear if PVP performs as a solubilizer or a crystallization inhibitor for hydrophilic drugs. For the lipophilic drug levonorgestrel, the skin flux profile from the saturated and PVP stabilized patches was the same, suggesting that PVP acts just as a drug solubilizer and does not produce supersaturation.
Keywords: Captopril; Levonorgestrel; Enhancer; Transdermal; Crystallization; Irritation testing;
The influence of protonation ratio on properties of carboxymethyl starch excipient at various substitution degrees: Structural insights and drug release kinetics by Elias Assaad; Mircea Alexandru Mateescu (75-84).
Carboxymethyl starch (CMS) with pH sensitivity modulated by the protonation ratio (PR 0–100%) and the degree of substitution (DS 0.07–0.20) was synthesized in aqueous medium. The properties of CMS excipient and the mechanism of acetaminophen release from monolithic tablets in simulated gastric fluid (SGF, pH 1.2) and in simulated intestinal fluid (SIF, pH 6.8) were investigated. Compared to sodium CMS, the protonated CMS provided a longer release time which increases with the increase of PR. Over storage time, the highly protonated CMS showed a decrease in solubility and a progressive structural alteration due to hydrogen bonded carboxyl groups. Simultaneously, an acceleration of release rate of formulated drug was observed. The CMS(DS 0.11) with PR up to 50% showed relatively low sensitivity to dissolution medium pH and sustained release pattern almost independent of tablet preincubation in SGF and of drug loading (20% and 40%). The CMS(DS 0.20) was more sensitive to pH and showed an accelerated release rate in SIF. For the CMS formulations, a diffusion mechanism was suggested in SGF, whereas in SIF the release was mostly controlled by swelling and erosion.
Keywords: Carboxymethyl starch; Excipient; Protonation ratio; Degree of substitution; Monolithic tablet; Drug delivery;
Critical role of water diffusion into matrix in external use iodine preparations by Yasuhiro Noda; Satoshi Fujii (85-91).
Iodine preparations for external use are recommended for treating pressure ulcers with manifestations of infection and necrosis. These ulcers abundantly produce wound exudates, which could be absorbed by water-soluble base. In this study we aimed to improve the previously reported methodologies for water absorption and new methodologies were developed in Franz diffusion cell with 100 kDa molecular weight cut-off (MWCO) membranes. Using these new methodologies water absorbing capacities of existing iodine preparations [povidone–iodine (PI) sugar ointment, iodine–potassium iodide (IKI) gel, cadexomer–iodine (CI) ointment] and another superabsorbent polymer dextranomer paste were evaluated. Water absorption indexes were 7.52, 1.98, 1.44 and 2.90 (mg/cm2/min0.5), respectively. With PI sugar ointment observed amount of water absorbed increased in a linear fashion over time. In contrast, with IKI gel, CI ointment and dextranomer paste observed amount of water absorbed decreased over time. When the observed amount of water absorbed was plotted against square of time, the lines of IKI gel and CI ointment became linear. With dextranomer paste the line became biphasic with 1-folding point. These results suggest that water diffusion into matrix is the rate limiting step in IKI gel, CI ointment and dextranomer paste, and that capacity of absorbing wound exudates could substantially differ among these ointments.
Keywords: Cadexomer–iodine; Povidone–iodine; Iodine–potassium iodide; Pressure ulcer; Water absorption;
Effect of DMSO on micellization, gelation and drug release profile of Poloxamer 407 by Tofeeq Ur-Rehman; Staffan Tavelin; Gerhard Gröbner (92-98).
The application of many recently developed or approved drugs and pharmaceuticals is seriously hampered by their low solubility in aqueous media. Hence, numerous promising pharmaceutical delivery systems (including novel “smart” systems based on poloxamer gels, which have highly advantageous thermo-reversible characteristics and low toxicity) cannot solubilize required doses of various drugs without additives such as co-solvents or salts. Therefore, we have studied the effects of dimethyl sulphoxide (DMSO) – a commonly used co-solvent during drug development stages – on the micellization, gelation and dissolution properties of aqueous poloxamer solutions. Differential scanning calorimetry and tube inversion experiments clearly showed that DMSO induces reductions in the critical micellization and gelation temperatures of poloxamer systems. In addition, high resolution solid state 1H Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) analyses provided indications of the specific chemical groups in the poloxamer affected by DMSO, and the molecular mechanism involved. The presence of DMSO accelerated dissolution of the pure gel in water and the release of a hydrophobic drug (flufenamic acid) from poloxamer gel, while it reduced the release of a hydrophilic drug (metoprolol tartrate).
Keywords: Poloxamer; Drug delivery; Micellization; DMSO; Calorimetry; NMR;
Effect of ethanol as a processing co-solvent on the PLGA microsphere characteristics by Archana Rawat; Diane J. Burgess (99-105).
The effect of ethanol, as an organic phase co-solvent, on the characteristics of dexamethasone containing poly(lactide-co-glycolide) (PLGA) microspheres prepared via the emulsion–solvent evaporation/extraction process has been evaluated. This study allowed determination of the maximum amount of ethanol that can be used to prepare radio-labeled dexamethasone microspheres without affecting their performance. Different ethanol co-solvent concentrations (0–43.75% (v/v)) were investigated and changes in the physicochemical properties and in vitro release profiles were determined. A significant decrease in particle size and drug loading was observed at 12.50% and 25% (v/v) ethanol concentrations, respectively. Morphological evaluation revealed the presence of drug crystals on the microsphere surfaces prepared using ethanol co-solvent concentrations of 18.75% (v/v) and higher. A high burst release was observed with these formulations due to the presence of drug crystals on microsphere surfaces. Various competing factors such as interfacial tension between methylene chloride and water, solubility of drug in the organic phase and the viscosity of the polymer phase contributed to the changes observed in microspheres characteristics at different ethanol co-solvent concentrations. It was determined that radio-labeled dexamethasone solution (in ethanol) can be used at concentrations up to 12.5% (v/v) of organic phase without any significant change in microsphere characteristics.
Keywords: Microspheres; Emulsion–solvent evaporation/extraction; Co-solvents; In vitro release; USP apparatus 4;
QSAR analysis of antitumor active amides and quinolones from thiophene series by B. Bertoša; M. Aleksić; G. Karminiski-Zamola; S. Tomić (106-114).
QSAR models for predicting antitumor activity of heterocyclic amides and quinolones from benzo[b]thiophene-, thieno[3,2-b]thiophene- and thieno[2,3-b], thiophene series against MiaPaCa-2 and MCF-7 cells were built. Complete dataset consisted of 59 compounds and several QSAR models with different predictive ability were derived. Beside standard approaches for building QSAR models, the approach based on a small dataset of 10 compounds selected regarding the results of principal component analysis was tested. The latter approach was shown as successful and can be useful for planning future experiments in order to speed up and simplify the search for new drug candidates. Based on the derived QSAR models, the most important properties for compound's antitumor activity against MiaPaCa-2 and MCF-7 cells were identified. Volume, sum of the hydrophobic surfaces and presence of the group that can be easily ionized in the pH range from 4 to 9, were found to be highly important for successful antitumor activity of the examined heterocyclic amides and quinolones. New compounds, with potentially higher biological activity against MiaPaCa-2 and MCF-7 cells, were proposed. Their activities were predicted using the derived QSAR models and the proposed compounds were shown as promising antitumor candidates.
Keywords: QSAR; VolSurf; Antitumor activity; Quinolones;
Potential neurotoxicity of nanoparticles by Yu-Lan Hu; Jian-Qing Gao (115-121).
With the rapid development of nanotechnology, there is a growing interest on the application of nanoparticles in various fields such as photonics, catalysis, magnetics, and biotechnology including cosmetics, pharmaceutics, and medicines. However, little is known about their potential toxicity to human health. Owing to their special properties, nanoparticles have the capacity to bypass the blood–brain barrier (BBB). However, the toxic effects of nanoparticles on central nervous system (CNS) function are still lacking. And the interactions of nanoparticles with the cells and tissues in CNS are poorly understood. Thus, neurotoxicity induced by nanoparticles is still a new topic that requires more attention. In this review, we summarized the pathways by which the nanoparticles could enter into the CNS and the recent investigations on the neurotoxicity of nanoparticles both in vitro and in vivo, as well as the potential mechanisms. Furthermore, the future direction in the neurotoxicity studies of nanoparticles is also discussed.
Keywords: Neurotoxicity; Nanoparticles; Polymer nanocarrier;
Dendrimer toxicity: Let's meet the challenge by Keerti Jain; Prashant Kesharwani; Umesh Gupta; N.K. Jain (122-142).
Dendrimers are well-defined, versatile polymeric architecture with properties resembling biomolecules. Dendritic polymers emerged as outstanding carrier in modern medicine system because of its derivatisable branched architecture and flexibility in modifying it in numerous ways. Dendritic scaffold has been found to be suitable carrier for a variety of drugs including anticancer, anti-viral, anti-bacterial, antitubercular etc., with capacity to improve solubility and bioavailability of poorly soluble drugs. In spite of extensive applicability in pharmaceutical field, the use of dendrimers in biological system is constrained because of inherent toxicity associated with them. This toxicity is attributed to the interaction of surface cationic charge of dendrimers with negatively charged biological membranes in vivo. Interaction of dendrimers with biological membranes results in membrane disruption via nanohole formation, membrane thinning and erosion. Dendrimer toxicity in biological system is generally characterized by hemolytic toxicity, cytotoxicity and hematological toxicity. To minimize this toxicity two strategies have been utilized; first, designing and synthesis of biocompatible dendrimers; and second, masking of peripheral charge of dendrimers by surface engineering. Biocompatible dendrimers can be synthesized by employing biodegradable core and branching units or utilizing intermediates of various metabolic pathways. Dendrimer biocompatibility has been evaluated in vitro and in vivo for efficient presentation of biological performance. Surface engineering masks the cationic charge of dendrimer surface either by neutralization of charge, for example PEGylation, acetylation, carbohydrate and peptide conjugation; or by introducing negative charge such as half generation dendrimers. Neutral and negatively charged dendrimers do not interact with biological environment and hence are compatible for clinical applications as elucidated by various studies examined in this review. Chemical modification of the surface is an important strategy to overcome the toxicity problems associated with the dendrimers. The present review emphasizes on the approaches available to overcome the cationic toxicity inherently associated with the dendrimers.
Keywords: Dendrimers; Cationic toxicity; Biocompatibility; Surface engineering;
Magnetic activated release of umbelliferone from lipid matrices by Dandan Yi; Pengyun Zeng; Timothy Scott Wiedmann (143-146).
Lipid matrices containing dispersed superparamagnetic iron oxide (SPIO) particles were investigated as a magnetic field-responsive drug delivery system. Lipid matrices were prepared by combining myristyl alcohol, fatty acid coated SPIO particles, and umbelliferone (UMB). With placement of the matrices into the release medium, initial UMB release was fast but fell to zero indicating a burst effect. With application of an alternating magnetic field, additional UMB was released. The rate and extent of magnetic field-stimulated release increased with UMB load but not SPIO content. Differences between oleic and myristic acid coated SPIO appeared to be a result of phase separation. UMB release coincided with matrix melting, which can be controlled by the SPIO content and external magnetic field as shown by theoretical analysis. While significant technological issues remain, the foundation for developing magnetic field-stimulated drug delivery systems has been established.
Keywords: Magnetic activated; Umbelliferone; Superparamagnetic particles; Magnetite; Myristyl alcohol;
The characteristics and mechanism of simvastatin loaded lipid nanoparticles to increase oral bioavailability in rats by Zhiwen Zhang; Huihui Bu; Zhiwei Gao; Yan Huang; Fang Gao; Yaping Li (147-153).
Simvastatin (SV), a cholesterol-lowering agent, has been widely used in the treatment of hypercholesterolemia, dyslipidemia and coronary heart disease, but SV shows the low oral bioavailability due to its poor aqueous solubility and extensive metabolism by cytochrome-3A system in intestinal guts and liver. In this work, SV loaded lipid nanoparticles (SLNs) with different components were designed to enhance its oral bioavailability, and the plasma concentration of SV and its active metabolite (simvastatin acid, SVA) was determined by LC–MS–MS method. The experimental results showed that SLNs were spherical nano-sized particles with high encapsulation efficiency (>95%). The in situ intestinal absorption indicated that the absorption of SLNs was greatly improved compared with that of free SV, and the absorption was changed with the site of the intestinal segments. SLNs could be uptaken into the enterocytes through both clathrin and caveolae mediated endocytosis pathways. The oral bioavailability of SV after its incorporation into the lipid nanoparticles was improved by 3.37-fold for SLNs I and 2.55-fold for SLNs II compared with that from free SV in rats, and that of the SVA was significantly enhanced as well. As a result, lipid nanoparticles could be a promising delivery system to enhance the oral bioavailability of simvastatin.
Keywords: Simvastatin; Simvastatin acid; Lipid nanoparticles; Intestinal absorption; Bioavailability;
Hydrotropic hyaluronic acid conjugates: Synthesis, characterization, and implications as a carrier of paclitaxel by Gurusamy Saravanakumar; Ki Young Choi; Hong Yeol Yoon; Kwangmeyung Kim; Jae Hyung Park; Ick Chan Kwon; Kinam Park (154-161).
Amphiphilic hyaluronic acid conjugates were synthesized as a potential drug carrier by chemical conjugation of an amine-terminated hydrotropic oligomer, which has a unique ability to enhance the solubility of paclitaxel (PTX), to a hyaluronic acid (HA) backbone using carbodiimide chemistry. The physicochemical properties of the hydrotropic hyaluronic acid (HydroHA) conjugates were investigated using 1H NMR, dynamic light scattering, transmission electron microscopy (TEM), and fluorescence spectroscopy. HydroHA conjugates could form self-assembled nanoparticles in an aqueous medium because of hydrophobic interactions among hydrotropic oligomers. Their particle sizes were in the range of 274–356 nm, depending on the degree of substitution (DS) of the hydrotropic oligomer. TEM images showed that particle morphology was spherical in shape. Critical aggregation concentrations of HydroHA conjugates ranged from 0.034 to 0.125 mg/mL, which decreased with an increase in the DS of the hydrotropic oligomer. The HydroHA conjugates were selectively taken up by the cancer cell line (SCC-7) over-expressing CD44, a hyaluronic receptor. The nanoparticles could encapsulate PTX up to 20.7 wt.% by the dialysis method. The in vitro release pattern of PTX from nanoparticles was significantly dependent on drug loading content, in which the release rate was lower for the nanoparticles that contained larger amounts of the drug. From the cytotoxicity test, it was found that the drug-loaded HydroHA nanoparticles exhibited stronger cytotoxicity to SCC-7 than to normal fibroblast cell (CV-1). These results suggest that HydroHA nanoparticles have potential as the carrier of PTX for cancer therapy.
Keywords: Hyaluronic acid; Hydrotropic oligomer; Paclitaxel; Self-assembled nanoparticles;
Synthesis and characterization of low-toxic amphiphilic chitosan derivatives and their application as micelle carrier for antitumor drug by Meirong Huo; Yong Zhang; Jianping Zhou; Aifeng Zou; Di Yu; Yiping Wu; Jing Li; Hong Li (162-173).
A new series of amphiphilically modified chitosan molecules with long alkyl chains as hydrophobic moieties and glycol groups as hydrophilic moieties (N-octyl-O-glycol chitosan, OGC) was synthesized for use as drug carriers. The chemical structure was characterized by Fourier transform infrared, 1H nuclear magnetic resonance, and elemental analysis. OGC could easily self-assemble to form nanomicelles in an aqueous environment and exhibited a low critical micellar concentration of 5.3–32.5 mg/L. The biocompatibility and low toxicity of OGC as excipient for the dosage forms aimed at i.v. administration were confirmed by hemolysis, acute toxicity and histopathological studies. Furthermore, the possibility of solubilizing paclitaxel (PTX), a water-insoluble antitumor drug, with OGC micelles was also explored. PTX was successfully loaded into OGC micelles by using a simple dialysis process. The drug-loading capacity of OGC and stability of drug-loaded micelles were significantly affected by the degree of substitution of alkyl chains. Moreover, a series of safety studies including hemolysis, hypersensitivity, maximum tolerated dose, acute toxicity, and organ toxicity revealed that the PTX-loaded OGC micelles had advantages over the commercially available injectable preparation of PTX (Taxol®), in terms of low toxicity levels and increased tolerated dose. Additionally, cytotoxicity studies showed that the PTX-loaded OGC micelles were comparable to the commercial formulation, but the blank micelles were far less toxic than the Cremophor EL vehicle. These results suggest that OGC is a promising carrier for injectable PTX micelles.
Keywords: N-octyl-O-glycol chitosan; Self-assembly; Drug delivery; Safety;
Histological bioanalysis for therapeutic effects of hybrid liposomes on the hepatic metastasis of colon carcinoma in vivo by Hideaki Ichihara; Kota Funamoto; Taku Matsushita; Yoko Matsumoto; Ryuichi Ueoka (174-178).
Therapeutic effects of hybrid liposomes (HL) composed of l-α-dimyristoylphosphatidylcholine (DMPC) and polyoxyethylene (23) dodecylether (C12(EO)23) on the metastasis of colon carcinoma (Colon26) cells were examined in vivo. Fluorescent labeled Colon26 cells were observed in the liver tissue of hepatic metastasis mouse models after the intrasplenic inoculation of the cells. Remarkably high therapeutic effects were obtained in the hepatic metastasis mouse models after the treatment with HL on the basis of relative liver weight and histological analysis of the liver tissue sections of mouse models with hematoxylin–eosin staining, Masson trichrome staining, and CEA immunostaining as a histochemical marker of metastatic colon carcinoma. Furthermore, no toxicity was observed in the hepatic metastasis mouse models after the intravenous injection of HL. Therapeutic effects of HL without any drugs on the hepatic metastasis were revealed on the basis of histological analysis for the first time in vivo.
Keywords: Hybrid liposomes; Chemotherapy; Hepatic metastasis; Histological bioanalysis; Apoptosis;
Preparation and characterization of vinpocetine loaded nanostructured lipid carriers (NLC) for improved oral bioavailability by Chun-Yang Zhuang; Ning Li; Mi Wang; Xiao-Ning Zhang; Wei-San Pan; Jun-Jie Peng; Yu-Sheng Pan; Xin Tang (179-185).
The purpose of this study is to develop an optimized nanostructured lipid carriers (NLC) formulation for vinpocetine (VIN), and to estimate the potential of NLC as oral delivery system for poorly water-soluble drug. In this work, VIN–loaded NLC (VIN–NLC) was prepared by a high pressure homogenization method. The VIN–NLC showed spherical morphology with smooth surface under transmission electron microscope (TEM) and scanning electron microscopic (SEM) analysis. The average encapsulation efficiency was 94.9 ± 0.4%. The crystallization of drug in NLC was investigated by powder X-ray diffraction and differential scanning calorimetry (DSC). The drug was in an amorphous state in the NLC matrix. In the in vitro release study, VIN–NLC showed a sustained release profile of VIN and no obviously burst release was observed. The oral bioavailability study of VIN was carried out using Wistar rats. The relative bioavailability of VIN–NLC was 322% compared with VIN suspension. In conclusion, the NLC formulation remarkably improved the oral bioavailability of VIN and demonstrated a promising perspective for oral delivery of poorly water-soluble drugs.
Keywords: Nanostructure lipid carriers; Vinpocetine; Oral bioavailability; Sustained release; Poorly water-soluble drugs;