International Journal of Pharmaceutics (v.319, #1-2)
Editorial Board (iii).
Towards a molecular characterization of pharmaceutical excipients: Mass spectrometric studies of ethoxylated surfactants by Klaus Raith; Christian E.H. Schmelzer; Reinhard H.H. Neubert (1-12).
The in-depth characterization of excipients is a prerequisite for their safe application in pharmaceutical products. In case of surfactants, this task can be a challenge, since many industrial products are mixtures of variable composition. In this work, mass spectrometric methods are applied to characterize some ethoxylated surfactants that are widely used by the pharmaceutical industry. Among them are ethoxylated fatty alcohols with ether structure (e.g., Brij®), ethoxylated fatty acids with ester structure (e.g., Myrj®), ethoxylated sorbitane fatty acid esters (e.g., Tween®), ethoxylated glycerides (e.g., Tagat®), and Triton® X-100. MALDI-TOF mass spectrometry is best suitable to obtain molecular mass distributions of polymeric products, namely those with higher molecular mass. Electrospray and nanoelectrospray molecular mass shows a greater tendency for multiple charges. However, it is best suitable for small MM products, and multiple charges have been de-convoluted successfully using the MaxEnt™ 3 algorithm. Tandem mass spectrometry helps to identify the chemical composition, e.g. for identification of acyl chains. The work is intended to serve as a reference for mass spectrometric characterization of surfactants in the course of R&D, validation or change control.
Keywords: Surfactants; Mass spectrometry; MALDI; ESI; Brij; Myrj; Tagat; Tween;
Surface analysis of powder binary mixtures with ATR FTIR spectroscopy by Odon Planinšek; Daniela Planinšek; Anamarija Zega; Matej Breznik; Stane Srčič (13-19).
Attenuated Total Reflectance Fourier Transform Infra Red spectroscopy (ATR FTIR) has been used for surface analysis of powder mixtures. The appearance of one component on the surface of the mixture in greater amounts than that expected from the mass or volume ratio was quantified. Coloured mixtures containing methyl orange were analysed. They contained proportions of components from 0% to 100% in steps of 10%. Mixtures of non-sieved powders of methyl orange and Povidone were dark red when containing only 20% of methyl orange, indicating that particles of methyl orange were present on the surface of the mixture in higher amounts than expected from the mass ratios. Mixtures of methyl orange and Mg stearate, on the other hand, were a light colour, showing the presence of more Mg stearate on the surface than expected. Visual observations correlated with semiquantitative surface concentration determination by ATR FTIR spectroscopy using specific peaks of each component. Quantitative determination of components on the surface of the mixture, using the Beer Lambert law, was possible when characteristic peaks for the first component did not overlap with those of the other component. A non-linear correlation between peak height and concentration of a component in a mixture was explained by distribution of the particle size of components. With a small component, the larger number of particles in the same volume allowed them to surround the larger particles of the second component. These conclusions were confirmed by preparing mixtures with non-coloured components (Povidone-Eudragit®, NaCl-Povidone, NaCl-Eudragit®). Results again correlated with the ATR FTIR spectroscopy measurements. It was additionally shown that a small proportion of finer particles can drastically influence the surface of powder mixtures, due to their large contribution to the specific surface area. ATR FTIR is thus demonstrated to be a useful method for studying surfaces of powder mixtures also in terms of process analytical technology (PAT).
Keywords: IR spectroscopy; ATR FTIR; Powder; Binary mixtures;
Modulation of drug release from glyceryl palmitostearate–alginate beads via heat treatment by Thaned Pongjanyakul; Srisagul Sungthongjeen; Satit Puttipipatkhachorn (20-28).
Diclofenac calcium alginate (DCA) beads containing glyceryl palmitostearate (GPS) were prepared by ionotropic gelation method. The effect of GPS amount and heat treatment on characteristics of the DCA beads was investigated. Incorporation of GPS into the DCA beads increased particle size and entrapment efficiency of diclofenac sodium (DS), but decreased water uptake in distilled water, and DS release rate. The heat treatment caused the DCA beads to be irregular shape particles and to possess higher water uptake. A slower release rate of DS in distilled water was found because of interaction of DS and alginate polymer matrix, and a restriction of water sorption into the inside region of the beads, which caused by the shrinkage of the beads after heating. However, the heat treatment did not affect particle shape and water uptake in distilled water of the 3%GPS–DCA beads. Differential scanning calorimetric study showed that GPS in the DCA beads was resolidified to different polymorph after cooling. Furthermore, the micro-Raman spectra indicated the existence of DS in the GPS matrix particles in the beads due to the partition of DS into the melted GPS during heat treatment. This led to a decrease in release rate of DS in pH 6.8 phosphate buffer and a change in DS release pattern in distilled water. Thus, not only the calcium alginate matrix, but also the resolidified GPS matrix in the alginate beads controlled the DS release from the 3%GPS–DCA beads with heat treatment.
Keywords: Calcium-alginate bead; Glyceryl palmitostearate; Heat treatment; Micro-Raman spectroscopy; Diclofenac sodium;
Controlled release of doxorubicin from thermosensitive poly(organophosphazene) hydrogels by Gyung D. Kang; Se H. Cheon; Soo-Chang Song (29-36).
Thermosensitive poly(organophosphazenes) bearing hydrophobic isoleucine ethyl esters group and hydrophilic α-amino-ω-methoxy-poly(ethylene glycol) of the molecular weight 550 along with hydrolysis-sensitive glycyl lactate ethyl esters have been synthesized for sustained delivery of anticancer drug. The aqueous solution of poly(organophosphazenes) containing doxorubicin, that represents chemotherapeutic agent for cancer treatment, was transformed into hydrogel with good gel strength at body temperature via hydrophobic interactions. Solubility of hydrophobic doxorubicin in the aqueous poly(organophosphazene) solution was dramatically improved as compared with that in PBS (0.01 M, pH 7.4). The hydrogel property of poly(organophosphazenes) was affected on incorporation of doxorubicin, resulting in increase of gelation temperature and decrease of gel strength. The release of loaded doxorubicin from the polymer hydrogel was significantly sustained over 20 days and the effect of gel strength, polymer concentration and drug concentration on the release rate were observed. The release of doxorubicin from the polymer gels was effectively controlled by the gel strength. As a result of investigating anticancer efficacy using cancer cell line of mouse lymphoblast of P388D1, the efficacy of doxorubicin was observed to be constant over a prolonged period of times for more than 30 days, indicating that the release of doxorubicin was sustained for a long time without any initial burst release, and that the delivery system was an excellent candidate for locally injectable gel–depot system.
Keywords: Thermosensitive hydrogel; Poly(organophosphazenes); Biodegradable; Doxorubicin; Locally inject able depot-forming system;
Induction of systemic and mucosal immune responses by intranasal administration of alginate microspheres encapsulated with tetanus toxoid and CpG-ODN by Mohsen Tafaghodi; S. Abolghasem Sajadi Tabassi; Mahmood Reza Jaafari (37-43).
In the induction of systemic and mucosal immunity, particulate antigens are more effective than soluble antigens; possibly because they are more efficiently endocytosed by mucosal-associated lymphoid tissue (MALT) M cells. In this study, we determined the systemic and mucosal immune responses in rabbits following intranasal immunization with encapsulated tetanus toxoid (TT) and CpG-ODN in alginate microspheres. The microspheres were less than 4 μm in diameter. Encapsulation efficiency of TT and CpG-ODN was determined as 47.7 ± 6.6 and 34.2 ± 7.4, respectively. Release of TT and CpG-ODN in a simulated model with nasal cavity was 14.2 ± 3.06 and 36.7 ± 2.4% after 4 h. Encapsulated TT preserved its intact structure, but its immunoreactivity was decreased to about 91 ± 5%. The highest serum IgG and antitoxin, and nasal lavage IgA titers were observed in groups immunized with microsphere formulations. CpG-ODN as an adjuvant could increase the serum IgG and antitoxin titers when co-administered with TT solution, but its co-encapsulation with TT in alginate microspheres failed to potentiate the systemic immune response while induced high IgA titers in nasal lavages. No hemolysis was occurred on incubation of alginate microspheres and human RBCs. Also after nasal administration of plain microspheres to human volunteers, no local irritation was observed. Intranasal administration of microspheres encapsulated with vaccines showed to be an effective way for inducing a variety of immune responses and that a strong systemic IgG and mucosal IgA responses can be induced in rabbits with intranasal administration of alginate microspheres encapsulated with TT.
Keywords: Nasal immunization; Alginate; CpG-ODN; Microsphere; Tetanus toxoid;
Nifedipine solid dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend for controlled drug delivery by Jingjun Huang; Rodney J. Wigent; Catherine M. Bentzley; Joseph B. Schwartz (44-54).
In order to elucidate the controlled-release mechanism of a poorly water-soluble drug from microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend prepared by a phase-separation method, nifedipine-loaded microparticles with different levels of drug loading were evaluated by micromeritic properties, drug physical state, matrix internal structure, drug dissolution, and release modeling. Drug release study indicated that nifedipine release from the microparticles followed the Fickian diffusion mechanism, which supported the study hypothesis that as a result of formation of a nifedipine molecular dispersion, nifedipine dissolution inside the matrix was no longer the rate-limiting step for drug release, and the drug diffusion in matrix became the slowest step instead. Moreover, study results indicated that even though drug loading did not significantly affect the microparticle size distribution and morphology, nifedipine release rate from those microparticles was more or less influenced by the level of drug loading, depending on matrix formulation. At lower levels of drug loading, nifedipine release was well described by the Baker and Lonsdale's matrix diffusion model for microspheres containing dissolved drug and nifedipine had a plasticizing effect on the polymers that caused an increase in drug effective diffusion coefficient with increasing drug loading. However, at higher levels of drug loading, probably due to formation of solid nifedipine domains in microparticles, a change in the release kinetics was observed.
Keywords: Nifedipine; Solid dispersion; Controlled release; Microparticles; Ethylcellulose; Eudragit RL;
NMR imaging of density distributions in tablets by A. Djemai; I.C. Sinka (55-62).
This paper describes the use of 1H nuclear magnetic resonance (NMR) for 3D mapping of the relative density distribution in pharmaceutical tablets manufactured under controlled conditions. The tablets are impregnated with a compatible liquid. The technique involves imaging of the presence of liquid which occupies the open pore space. The method does not require special calibration as the signal is directly proportional to the porosity for the imaging conditions used. The NMR imaging method is validated using uniform density flat faced tablets and also by direct comparison with X-ray computed tomography. The results illustrate (1) the effect of die wall friction on density distribution by compressing round, curved faced tablets using clean and pre-lubricated tooling, (2) the evolution of density distribution during compaction for both clean and pre-lubricated die wall conditions, by imaging tablets compressed to different compaction forces, and (3) the effect of tablet image on density distribution by compressing two complex shape tablets in identical dies to the same average density using punches with different geometries.
Keywords: NMR imaging; Tablet; Compaction; Density distribution; Die wall friction;
Cyclodextrin-containing poly(ethyleneoxide) tablets for the delivery of poorly soluble drugs: Potential as buccal delivery system by Brunella Cappello; Giuseppe De Rosa; Lucia Giannini; Maria Immacolata La Rotonda; Giuseppe Mensitieri; Agnese Miro; Fabiana Quaglia; Roberto Russo (63-70).
The aim of this work was to develop a tablet for the buccal delivery of the poorly soluble drug carvedilol (CAR), based on poly(ethyleneoxide) (PEO) as bioadhesive sustained-release platform and hydroxypropyl-β-cyclodextrin (HPβCD) as modulator of drug release. As first, PEO tablets loaded with CAR/HPβCD binary systems with different dissolution properties were tested for CAR and HPβCD release features and compared to PEO tablets containing only CAR. When the drug was incorporated as CAR/HPβCD freeze-dried product, all CAR content was released from the tablet in about 10 h, displaying a constant release regimen after a transient. The effect of HPβCD incorporation on the release mechanism, was rationalized on the basis of the interplay of different physical phenomena: erosion and swelling of the tablet, drug dissolution, drug counter-diffusion and complex formation. In the second part of the study, the potential of HPβCD-containing PEO tablets as buccal delivery system for CAR was tested. It was found that the incorporation of HPβCD in the tablet did not alter significantly its good adhesion properties. The feasibility of buccal administration of CAR was assessed by permeation experiments on pig excised mucosa. The amount of CAR permeated from PEO tablet was higher in the case of HPβCD-containing tablets, the maximum value being obtained for CAR/HPβCD freeze-dried system. Our results demonstrate that, when the tablet is employed as transmucosal system, the role of drug dissolution enhancement in the hydrated tablet is much more relevant than in solution for increasing the delivery rate.
Keywords: Carvedilol; Hydroxypropyl-β-cyclodextrin; Mucoadhesion; Buccal delivery;
Novel design of osmotic chitosan capsules characterized by asymmetric membrane structure for in situ formation of delivery orifice by Gen-Ming Wang; Chien-Ho Chen; Hsiu-O Ho; Sheng-Shi Wang; Ming-Thau Sheu (71-81).
In this study, chitosan capsules with asymmetric membrane to induce osmotic effects and in situ formation of the delivery orifice were optimally prepared and characterized. Chitosan capsules were formed on stainless steel mold pins by dipping the pins into a chitosan solution followed by forming asymmetric structure by dipping into a quenching solution containing tripolyphosphate (TPP) to cause an ionic cross-linking reaction between the outer layer of chitosan and TPP. Factors influencing the properties of the capsule membrane, such as the molecular weight of chitosan, the dipping solution and dipping time, and the quenching solution and time, were optimized to successfully produce osmotic chitosan capsules with asymmetric membrane using chitosans that possessed different viscosities. In situ formation of a delivery orifice on the asymmetric membrane of the chitosan capsule was proven by the observation of a jet stream of chlorophyll being released from the capsule. Drugs with different solubility were selected, and a linear correlation between drug solubility and the initial drug release rate calculated from the slope of the drug release profile was used to verify that the delivery orifices that were in situ formed on the asymmetric membrane of the chitosan capsules induced by osmotic effect was responsible for the drug release. Water permeability across the optimally produced asymmetric membrane of the capsule from chitosan of 500 cps (300–700 cps) quenched with TPP for 30 min (C500/TPP30) was determined to be 1.40 × 10−6 cm2 h−1 atm−1 at 37.0 ± 0.5 °C. The encapsulation of poorly water-soluble drugs, felodipine (FE) and nifedipine (NF), in such an asymmetric chitosan capsule was capable of creating a sufficient osmotic effect to activate the release of the drug with the addition of SLS and HPMC. The multiple regression equations of maximal release percent at 24 h for FE and NF confirmed that both sodium lauryl sulfate (SLS) and hydroxypropyl methylcellulose (HPMC) positively influenced this response factor, and the effect of SLS was greater than that of HPMC.
Keywords: Chitosan; Asymmetric membrane; Osmotic; In situ orifice formation; Poorly soluble drugs;
QSPR models for the prediction of apparent volume of distribution by Taravat Ghafourian; Mohammad Barzegar-Jalali; Siavoush Dastmalchi; Tina Khavari-Khorasani; Nasim Hakimiha; Ali Nokhodchi (82-97).
An estimate of volume of distribution (V d) is of paramount importance both in drug choice as well as maintenance and loading dose calculations in therapeutics. It can also be used in the prediction of drug biological half life. This study employs quantitative structure–pharmacokinetic relationship (QSPR) techniques for the prediction of volume of distribution. Values of V d for 129 drugs were collated from the literature. Structural descriptors consisted of partitioning, quantum mechanical, molecular mechanical, and connectivity parameters calculated by specialized software and pK a values obtained from ACD labs/log D database. Genetic algorithm and stepwise regression analyses were used for variable selection and model development. Models were validated using a leave-many-out procedure. QSPR analyses resulted in a number of significant models for acidic and basic drugs separately, and for all the drugs. Validation studies showed that mean fold error of predictions for the selected models were between 1.79 and 2.17. Although separate QSPR models for acids and bases resulted in lower prediction errors than models for all the drugs, the external validation study showed a limited applicability for the equation obtained for acids. Therefore, the universal model that requires only calculated structural descriptors was recommended. The QSPR model is able to predict the volume of distribution of drugs belonging to different chemical classes with a prediction error similar to that of the other more complicated prediction methods including the commonly practiced interspecies scaling. The structural descriptors in the model can be interpreted based on the known mechanisms of distribution and the molecular structures of the drugs.
Keywords: Volume of distribution; QSPR; Pharmacokinetics; V d; In silico; Prediction;
Co-solubilization of poorly soluble drugs by micellization and complexation by Venkatramana M. Rao; M. Nerurkar; S. Pinnamaneni; F. Rinaldi; K. Raghavan (98-106).
The use of combined approach of surfactants and cyclodextrins in solubilization of poorly soluble drugs has been described in literature. In this report, a mathematical model has been developed to provide the quantitative basis for this approach. First, by way of hypothetical examples and simulations, the influence of various interaction parameters on the phase solubility profile is presented. Additionally, the model results are compared with (a) results reported by Yang et al., with NSC-639829, sodium lauryl sulfate (SLS) and sulfobutyl-ether-β-cyclodextrin ((SBE)7M-β-CD) and (b) solubility of methylprednisolone, a model poorly soluble drug, in the presence of its water-soluble ‘surfactant-like’ prodrug, methylprednisolone 21-hemisuccinate, and (SBE)7M-β-CD. The model shows good agreement with experimental data. Furthermore, theoretical simulations show that the combined solubility is less than the sum of the individual solubility values in cyclodextrins and surfactants. Based on the hypothetical case and the two examples, the factors affecting the phase solubility profile in mixed solutions of surfactants and cyclodextrins are presented. Finally, the limitations of the model to explain co-solubilization by surfactants and cyclodextrins are discussed.
Keywords: Surfactant; Cyclodextrin; Water-soluble prodrug; Micellization; Complexation; Solubilization;
The delivery of ketoprofen from a system containing ion-exchange fibers by Limin Yu; Sanming Li; Yue Yuan; Yi Dai; Hongzhuo Liu (107-113).
A postulated model for transdermal delivery using ion-exchange fibers as controlling device was designed, and the main objective of this study was to assess the rationality of the model. The release rates of ketoprofen from the carbopol-based gel vehicles containing ion-exchange fibers to which the ketoprofen had been bound have been determined across 0.22 μm microporous membrane. The fluctuation of the release rate of ketoprofen from the vehicles was much lower compared with that of simple gels, though the cumulative amount of ketoprofen delivery was less. Additional ions could increase the rate and extent of ketoprofen delivery. The iontophoretically assisted transport of ketoprofen across rat skin was also studied and found to be favorable to ketoprofen permeation. According to the tested model, the ion-layer could enhance the ketoprofen delivery and satisfactory results were achieved.
Keywords: Transdermal; Iontophoresis; Gel; Ion-exchange fibers; Ketoprofen;
Solid-state properties and crystallization behavior of PHA-739521 polymorphs by Changquan (Calvin) Sun (114-120).
PHA-739521 is an experimental compound that exhibits polymorphism. The two anhydrous crystal forms, I and II, are characterized using powder X-ray diffractometry, thermal analyses, moisture sorption gravimetry. Both Forms I and II are non-hygroscopic and are stable to compaction pressure. The melting temperature is about 152 °C for Form I and 168 °C for Form II. Forms I and II are enantiotropically related where Form I is more stable below a transition temperature of approximately 70 °C. Crystallization behavior of this compound from solutions and during heating is also studied. Information obtained is used to design an appropriate crystallization process to successfully manufacture desired polymorph at large scale.
Keywords: Polymorph; PHA-739521; Transition temperature; Crystals; Thermal analysis; Physical characterization; Solid state;
Evaluation of hybrid liposomes-encapsulated silymarin regarding physical stability and in vivo performance by Mohamed S. El-Samaligy; Nagia N. Afifi; Enas A. Mahmoud (121-129).
Silymarin, a known standardized extract obtained from seeds of Silybum marianum is used in treatment of liver diseases of varying origins. Aiming at improving its poor bioavailability from oral products, silymarin hybrid liposomes are introduced in this work for buccal administration after investigating their stability and in vivo hepatoprotective efficiency. Silymarin loaded hybrid liposomes composed of lecithin (L), cholesterol (Ch), stearyl amine (SA) and Tween 20 (T20) in molar ratio of (9:1:1:0.5) were prepared. Their stability upon storage was studied at 4 °C and at ambient conditions. Stored samples were analyzed for percent encapsulation, drug release, particle size, turbidity measurement and visual changes. Characterization of the blend between phospholipid and silymarin was done using FT-IR and DSC which indicated a possible interaction. The stabilized formula of silymarin hybrid liposomes was evaluated upon buccal administration regarding its hepatoprtective activity against carbon tetrachloride-induced oxidative stress in albino rats. The degree of protection was measured using biochemical parameters like serum glutamic oxalacetate transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT). The introduced silymarin hybrid liposomes produced a significant decrease in both transaminase levels when challenged with CCl4 (intraperitonially) in comparison with orally administered silymarin suspension. This improvement was also confirmed histopathologically.
Keywords: Silymarin; Hybrid liposomes; Stability; Hepatoprotective activity;
Retinol-encapsulated low molecular water-soluble chitosan nanoparticles by Dong-Gon Kim; Young-Il Jeong; Changyong Choi; Sung-Hee Roh; Seong-Koo Kang; Mi-Kyeong Jang; Jae-Woon Nah (130-138).
This aim of this study was to encapsulate retinol into chitosan nanoparticles and reconstitute it into aqueous solution. Retinol-encapsulated chitosan nanoparticles were prepared for application of cosmetic and pharmaceutical applications. Retinol-encapsulated chitosan nanoparticle has a spherical shape and its particle sizes were around 50–200 nm according to the drug contents. Particle size was increased according to the increase of drug contents. Solubility of retinol is able to increase by encapsulation into chitosan nanoparticles more than 1600-fold. It was suggested that retinol was encapsulated into chitosan nanoparticles by ion complex as a result of FT-IR spectra. Specific peak of chitosan at 1590 cm−1 was divided to semi-doublet due to the electrostatic interaction between amine group of chitosan and hydroxyl group of retinol. At 1H NMR spectra, specific peaks of retinol disappeared when retinol-encapsulated chitosan nanoparticles were reconstituted into D2O while specific peaks both of retinol and chitosan appeared at D2O/DMSO (1/4, v/v) mixture. XRD patterns also showed that crystal peaks of retinol were disappeared by encapsulation into chitosan nanoparticles. Retinol-encapsulated nanoparticles were completely reconstituted into aqueous solution as same as original aqueous solution and zeta potential of reconstituted chitosan nanoparticles was similar to their original solution. At HPLC study, retinol was stably and efficiently encapsulated into chitosan nanoparticles.
Keywords: Water-soluble chitosan; Retinol; Polyion complex; Nanoparticles;
Inhibition of malarial topoisomerase II in Plasmodium falciparum by antisense nanoparticles by Florian Föger; Wilai Noonpakdee; Brigitta Loretz; Songwut Joojuntr; Willi Salvenmoser; Marlene Thaler; Andreas Bernkop-Schnürch (139-146).
New effective antimalarial agents are urgently needed due to increasing drug resistance of Plasmodium falciparum. Phosphorothioate antisense oligodeoxynucleotides (ODNs) silencing of malarial topoisomerase II gene have shown to possess promising features as anti malarial agents. In order to improve stability and to increase intracellular penetration, ODNs were complexed with the biodegradable polymer chitosan to form solid nanoparticles with an initial diameter of ∼55 nm. The particle zetapotential depended on the chitosan/ODN mass ratio. Nanoparticles with mass ratio of 2:1 displayed a positive surface charge (+15 mV) whereas particles with 1:1 mass ratio were negatively charged (−20 mV). Additionally nanoparticles were found to protect ODNs from nuclease degradation. P. falciparum K1 strain was exposed to the chitosan/ODN-nanoparticles for 48 h in order to examine the effects of chitosan/antisense (AS) and chitosan/sense (S) oligodeoxynucleotide nanoparticles on malaria parasite growth. Both negatively and positively charged antisense nanoparticles as well as free antisense ODNs (in a final concentration of 0.5 μM) showed sequence specific inhibition compared with sense sequence controls. However, nanoparticles were much more sequence specific in their antisense effect than free ODNs. Nanoparticles with negative surface charge exhibited a significantly stronger inhibitory effect (∼87% inhibition) on the parasite growth in comparison to the positive ones (∼74% inhibition) or free ODNs (∼68% inhibition). This is the first study demonstrating the susceptibility of P. falciparum to antisense nanoparticles.
Keywords: Plasmodium falciparum; Malaria; Nanotechnology; Chitosan nanoparticles; Antisense;
Novel polymeric micelles for hydrophobic drug delivery based on biodegradable poly(hexyl-substituted lactides) by Thomas Trimaille; Karine Mondon; Robert Gurny; Michael Möller (147-154).
Novel amphiphilic methoxy-poly(ethylene glycol)-poly(hexyl-substituted lactides) block copolymers were synthesized by ring-opening polymerization (ROP) of mono and dihexyl-substituted lactide (mHLA and diHLA) in bulk at 100 °C in the presence of tin(II) 2-ethylhexanoate (Sn(Oct)2) as catalyst and methoxy-poly(ethylene glycol) (MPEG) as initiator. MPEG-PmHLA and MPEG-PdiHLA copolymers of predictable molecular weights and narrow polydispersities were obtained, as shown by 1H NMR and GPC. DSC experiments showed that the MPEG-PHLA block-copolymer presents a bulk microstructure containing MPEG domains segregated from the PHLA domains. Micelles were successfully prepared from these block copolymers, with sizes ranging from 30 to 80 nm. The critical micellar concentration (CMC) was found to decrease with the increasing number of hexyl groups on the polyester block (MPEG-PLA > MPEG-PmHLA > MPEG-PdiHLA) for copolymers of the same composition and molecular weight. The hydrophobicity of the micelle core in dependence of the number of hexyl groups along the PLA chain was evidenced by absorbance experiments with the incorporation of the dye Nile Red. These novel amphiphilic copolymers are interesting for micellar drug delivery and especially in regard to optimized hydrophobic drug loadings, as it was shown for griseofulvin as a model drug.
Keywords: Micelles; Drug delivery; Substituted poly(lactides); Poly(ethylene glycol); Biodegradable polymers; Biocompatible polymers; Hydrophobic drugs; Nile Red; Griseofulvin;
Formulation and cytotoxicity of doxorubicin nanoparticles carried by dry powder aerosol particles by Shirzad Azarmi; Xia Tao; Hua Chen; Zhaolin Wang; Warren H. Finlay; Raimar Löbenberg; Wilson H. Roa (155-161).
Regional drug delivery via dry powder inhalers offers many advantages in the management of pharmaceutical compounds for the prevention and treatment of respiratory diseases. In the present study, doxorubicin (DOX)-loaded nanoparticles were incorporated as colloidal drug delivery system into inhalable carrier particles using a spray-freeze-drying technique. The cytotoxic effects of free DOX, carrier particles containing blank nanoparticles or DOX-loaded nanoparticles on H460 and A549 lung cancer cells were assessed using a colorimetric XTT cell viability assay. The mean geometric carrier particle size of 10 ± 4 μm was determined using confocal laser scanning microscopy. DOX-loaded nanoparticles had a particle size of 173 ± 43 nm after re-dissolving of the carrier particles. Compared to H460 cells, A549 cells showed less sensitivity to the treatment with free DOX. The DOX-nanoparticles showed in both cell lines a higher cytotoxicity at the highest tested concentration compared to the blank nanoparticles and the free DOX. The cell uptake of free DOX and DOX delivered by nanoparticles was confirmed using confocal laser scanning microscopy. This study supports the approach of lung cancer treatment using nanoparticles in dry powder aerosol form.
Keywords: Cytotoxicity; Doxorubicin; Nanoparticles; Powder inhalation; Spray-freeze drying; Lung cancer cells;
Preparation of silymarin proliposome: A new way to increase oral bioavailability of silymarin in beagle dogs by Xiao Yan-yu; Song Yun-mei; Chen Zhi-peng; Ping Qi-neng (162-168).
The aim of the present study was to find a method to increase oral bioavailability of silymarin, that is to say, by the preparation of silymarin proliposome and to compare the pharmacokinetic characteristics and bioavailability after oral administration of silymarin proliposome and silymarin in beagle dogs. Silymarin proliposome was prepared by the film-deposition on carriers. After the proliposome was contacted with water, the silymarin liposome suspensions formed automatically. The tests of physicochemical properties including SEM, TEM, encapsulation efficiency, dissolution studies, particle size of the reconstituted liposome and stability of the silymarin proliposome were determined by laser-particle-sizer, HPLC, etc. The concentrations of silymarin in plasma of beagle dogs and its pharmacokinetic behaviors after oral administration of silymarin liposome suspensions and silymarin were studied by RP-HPLC. The pharmacokinetic parameters were computed by software program 3p97. The encapsulation efficiency of silymarin liposome could be more than 90%, with an average particle size of about 196.4 nm and the proliposome appeared a very stability at 40 °C during 3 months. It was found that mean plasma concentration–time curves of silymarin after oral administration of liposome suspensions and silymarin in beagle dogs were both in accordance with open two-compartments model and first-order absorption. Pharmacokinetic parameters of silymarin proliposome and silymarin in beagle dogs were T max both 30 min; C max 472.62 and 89.78 ng mL−1; and AUC0-∞ 2606.21 and 697 ng mL−1 h, respectively. The high bioavailability of silymarin proliposome could be obtained by oral administration. Silymarin proliposome was stable and did enchance the gastrointestinal absorption of silymarin.
Keywords: Silymarin; Proliposome; Oral bioavailability; Beagle dogs; Pharmacokinetics;
Estimation of the aqueous solubility of weak electrolytes by Neera Jain; Gang Yang; Stephen G. Machatha; Samuel H. Yalkowsky (169-171).
Jain and Yalkowsky [Jain, N., Yalkowsky, S.H., 2001. Estimation of the aqueous solubility. I. Application to organic non-electrolytes. J. Pharm. Sci. 90, 234–252.] demonstrated that the general solubility equation (GSE) can be used to estimate the aqueous solubility of organic non-electrolytes. In this study the applicability of the GSE was extended to weak electrolytes. It is demonstrated that the GSE estimates the aqueous solubility of 949 compounds, including 367 weak electrolytes with an AAE of 0.58. It is also shown that the intrinsic solubilities of weak acids for which the pK a + log S w ≤ 0 and for weak bases for which pK a − log S w ≤ 14 are within a factor of 2 of the total solubilities.
Keywords: Solubility; GSE; Weak electrolytes; pKa;