International Journal of Pharmaceutics (v.282, #1-2)

Polymer microspheres for controlled drug release by S. Freiberg; X.X. Zhu (1-18).
Polymer microspheres can be employed to deliver medication in a rate-controlled and sometimes targeted manner. Medication is released from a microsphere by drug leaching from the polymer or by degradation of the polymer matrix. Since the rate of drug release is controlled by these two factors, it is important to understand the physical and chemical properties of the releasing medium. This review presents the methods used in the preparation of microspheres from monomers or from linear polymers and discusses the physio-chemical properties that affect the formation, structure, and morphology of the spheres. Topics including the effects of molecular weight, blended spheres, crystallinity, drug distribution, porosity, and sphere size are discussed in relation to the characteristics of the release process. Added control over release profiles can be obtained by the employment of core-shell systems and pH-sensitive spheres; the enhancements presented by such systems are discussed through literature examples.
Keywords: Polymer microspheres; Microsphere preparation; Drug delivery; Drug release rate;

The effects of molecular weight and porosity on the degradation and drug release from polyglycolide by Julia Braunecker; Mohamed Baba; Georgina E. Milroy; Ruth E. Cameron (19-34).
This paper explores the influence of initial molecular weight and porosity on the release of the drug, theophylline, from polyglycolide (PGA). PGA was made by a variety of processes to vary the molecular weight and was blended with NaCl with different crystal sizes and in different proportions to vary the pore size and volume. Overall, results showed that decreasing the molecular weight and increasing the pore size and volume increased the rate of drug release. The exact variation of these trends agreed well with the previously established four-stage degradation mechanism for PGA, but was more complex than a simple linear behaviour. Because both the molecular weight and the porosity of PGA have a substantial influence on the polymer degradation, and can be varied in a controlled manner, these parameters can play an important role in developing PGA as a controlled drug delivery material with tailored drug release.
Keywords: Polyglycolide; PGA; Porosity; Molecular weight; Controlled drug release; Theophylline;

Control, communication and monitoring of intravaginal drug delivery in dairy cows by Peter S. Cross; Rainer Künnemeyer; Craig R. Bunt; Dale A. Carnegie; Michael J. Rathbone (35-44).
We present the design of an electronically controlled drug delivery system. The intravaginally located device is a low-invasive platform that can measure and react inside the cow vagina while providing external control and monitoring ability. The electronics manufactured from off the shelf components occupies 16 mL of a Theratron syringe. A microcontroller reads and logs sensor data and controls a gascell. The generated gas pressure propels the syringe piston and releases the formulation. A two way radio link allows communication between other devices or a base station. Proof of principle experiments confirm variable-rate, arbitrary profile drug delivery qualified by internal sensors. A total volume of 30 mL was dispensed over a 7-day-period with a volume error of ±1 mL or ±7% for larger volumes. Delivery was controlled or overridden via the wireless link, and proximity to other devices was detected and recorded. The results suggest that temperature and activity sensing or social grouping determined via proximity can be used to detect oestrus and trigger appropriate responses.
Keywords: Drug delivery; Controlled release; Cow; Oestrus; Telemetry; Radio;

Bioadhesive properties and rheology of polyether-modified poly(acrylic acid) hydrogels by Lev Bromberg; Marina Temchenko; Valery Alakhov; T.Alan Hatton (45-60).
Transient rheological properties and mucoadhesion of hydrogels composed of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) (PEO–PPO–PEO, or Pluronic) block copolymers and poly(acrylic acid) were explored. Nine Pluronic copolymers ranging in nominal molecular weight and PPO/PEO content were grafted to PAA through CC bonds, with or without the use of divinyl cross-linker, ethylene glycol dimethacrylate (EGDMA). The hydrogel elasticity increased with the PPO content in the copolymers, as well as in the presence of EGDMA. Tensile tests were conducted to measure the fracture strength and the work of adhesion between the hydrogels and rat intestinal tissue. The fracture strength was proportional to the gel pseudoequilibrium modulus and depended on the nominal length of the PPO segments in the parent Pluronic copolymer. The work of mucoadhesion and gel cohesion declined with the loss angle measured in oscillatory shear experiments. The length of the PEO segments in Pluronic affected the work of adhesion. Applications of the Pluronic-PAA gels as vehicles in oral drug delivery are discussed. The longest Pluronic copolymers bonded to PAA resulted in copolymeric gels with strongest mucoadhesive properties.
Keywords: Poly(ethylene oxide)-b-poly(propylene oxide)-b-(polyethylene oxide)-g-poly(acrylic acid) copolymers (CAS #186810-81-1); Hydrogels; Mucoadhesion; Cohesion; Rheology; Rat intestine;

Microspheres were prepared from paclitaxel and binary polymer blends incorporating 1, 3, 40k and 100k g/mol PLLA. Thermal analysis was performed by DSC and in vitro paclitaxel release profiles were determined at 37 °C in phosphate buffer using an HPLC assay. In microspheres made with 3k/40k PLLA blends, the glass transition (T g), crystallinity and melting temperature (T m) all decreased with an increasing proportion of low molecular weight polymer in the blend. Similar trends were observed for 1k/100k blends. T m values ranged from 175 to 110 °C and T g values between 66 and 37 °C. However, for 1k/100k blends, melting point depression was linearly dependent on blend composition when plotted as 1/T m = 0.000109 × (%1k in blend) + 0.0223, R 2 = 0.97. A similar plot with data from the 3k/40k system yielded a non-linear relationship. Furthermore, the decrease in T g for both 1k/100k and 3k/40k blends followed the Fox equation, although experimental values were consistently 1–2 °C above predicted values. Paclitaxel release from microspheres made with a 1k/100k blend occurred in four distinct phases: a burst phase (day 0), a slower phase, a second burst (day 35) and a second slower phase (until day 70). The second burst coincided with visible degradation of the microspheres. Blends of low and high molecular weight PLLA display thermal properties indicating that 1k g/mol PLLA behaves as a diluent when blended with 100k g/mol PLLA, being excluded from the crystalline domains in the polymer matrix. In contrast, 3k g/mol PLLA is incorporated in both amorphous and crystalline regions of the polymer blend. Paclitaxel release profiles from 1k/100k PLLA microspheres demonstrate a multiphase profile due to the effects of both diffusion and degradation controlled release mechanisms.
Keywords: Polymer blending; PLLA; Drug release; Thermal properties; Paclitaxel; Microsphere;

Understanding the polymorphic behavior of pharmaceutical solids during the crystallization process and further in post-processing units is crucial to meet medical and legal requirements. In this study, an analytical technique was developed for determining the composition of two solid forms of ranitidine hydrochloride using two peaks of Fourier transform infrared (FTIR) spectra without the need to grind the samples. Solubility studies of ranitidine hydrochloride showed that Form 2 has a higher solubility than Form 1. Solution-mediated transformation is very slow and occurs from Form 2 to Form 1 and not the reverse. No solid–solid transformation was observed due to grinding or compressing the pure samples of either forms and of a 50/50 wt.% mixture. Grinding was found to be a proper technique for increasing the bulk solid density of the ranitidine hydrochloride without the risk of solid–solid transformation. Dissolution rate found to be equally fast for both forms.The solubility data were modeled using the group contribution parameters and UNIversal QUAsi-Chemical (UNIQUAC) theory. There was a good agreement between the experimental solubility data of ranitidine hydrochloride and the results of UNIQUAC equation.
Keywords: Ranitidine hydrochloride; Polymorphic transformation; Solubility measurement and prediction; UNIQUAC;

Pharmacokinetics of a cephalone (CQ-M-EPCA) in rats after oral, intraduodenal and intravenous administration by B. Pérez-Guillé; L.H. Sumano; F. Villegas-Alvarez; R. Soriano-Rosales; J.F. González-Zamora; M. Jiménez-Bravo-Luna; A. Carmona-Mancilla; C.L. Ocampo (87-94).
As part of the development of a new series of antibacterial agents derived from coupling a β-lactamic precursor with a fluoroquinolone and named cephalones, the pharmacokinetics of one derivate: CQ-M-EPCA in rats after intravenous, intragastric and intraduodenal routes, was carried out. After the IV injection of 20 mg/kg or 40 mg/kg of this cephalone, plasma concentrations at the time zero (C p0) were 3.1 and 11.26 μg/ml, respectively. Plasma concentrations decreased rapidly to almost disappear in both instances. Forty-five minutes later, a surge in concentrations, in the 40 mg/kg group, with a maximal plasma concentration (C pmax) of 2.97 μg/ml was observed. An elimination half-life (T (1/2)el) of 2.36 ± 0.33 h. was calculated. The drug was undetected by the ninth hour. Intragastric administration of the drug resulted in C pmax of 3.78 ± 0.26 μg/ml with a time to reach C pmax (T max) of 25 min and T (1/2)el = 3.22 h. Same variables after intraduodenal administration were C pmax 4.71 μg/ml; T max 1 h, and T (1/2)el 3.41 h. Outstandingly high bioavailabilities after intragastric and intraduodenal administration (169 and 246%, respectively), together with the shape of the concentration versus time profiles after IV administration suggest that the drug undergoes a complex redistribution phenomenon, while showing high tissue diffusion with an apparent volume of distribution of 3.33 l/kg.
Keywords: Pharmacokinetics; Cephalone; CQ-M-EPCA; Rat;

Influence of human nail etching for the assessment of topical onychomycosis therapies by Michael A. Repka; Praveen K. Mididoddi; Steven P. Stodghill (95-106).
The purpose of this investigation was to study the physico-chemical properties of hot-melt extruded films containing ketoconazole and to determine the influence of ‘nail etching’ on film bioadhesion and drug permeability for the assessment of topical onychomycosis therapies. Hot-melt extrusion (HME) was used to prepare films containing 20% w/w ketoconazole. Ketoconazole 0.125% gel was also prepared using Carbopol® 974P NF. Films were processed at a temperature range of 115–120 °C utilizing a Killion extruder (KLB-100), and were evaluated for post-extrusion drug content, content uniformity, bioadhesion, thermal behavior and nail drug permeation. The extruded films demonstrated excellent content uniformity and post-processing drug content. Tensile and peel tests were recorded to determine the bioadhesive profiles. In this study, work of adhesion and peak adhesive force determinations using the peel tests provided more sensitive results for evaluating the bioadhesivity of the HME films than the tensile tests. The in vitro permeability profiles have demonstrated, that nail samples treated with an ‘etchant’ demonstrated a significant increase in drug permeability compared to control. Differential scanning calorimetry (DSC) thermograms indicated that ketoconazole was in solid solution within the HME films. These findings are encouraging for the future design and formulation of novel drug delivery systems for the topical treatment of onychomycosis.
Keywords: Onychomycosis; Nail; Hot-melt extrusion; Bioadhesion; Permeability; Etching; Ketoconazole; Differential scanning calorimetry (DSC);

Effect of particle morphology on the triboelectrification in dry powder inhalers by Matti Murtomaa; Velipekka Mellin; Päivi Harjunen; Tapio Lankinen; Ensio Laine; Vesa-Pekka Lehto (107-114).
Electrostatic charge of lactoses of different particle morphology and amorphous contents were measured during actuation from two different dry powder inhalers (DPIs). Triboelectric studies may give important information when new inhaler devices, materials and formulations are designed in order to improve the drug deposition. Two inhalers, Taifun™ (Focus Inhalation Oy, Finland) and Clickhaler™ (Innovata Biomed Ltd., UK) were filled with lactose powders which were spray dried from different solutions or suspensions of lactose, ethanol and water. Differences in the amorphous contents were determined with isothermal microcalorimetry (IMC) and X-ray diffraction (XRD) and the particle morphology was examined with laser diffraction and electron microscopy (SEM). Samples were actuated from the inhalers at given intervals into the Faraday pail and the generated charges were recorded. Increase in the water concentration of the feed suspension had negligible effect on the charging until it exceeded 70%. Reproducibility of the measurement was found to be better with samples of homogenous particles and higher crystallinity while more amorphous samples with different morphology and wide particle size distribution showed change in the sign of the charge in addition to higher variations of the magnitude. In this study we show that different inhalers, as well as the morphology of the lactose powder, has noticeable effects on the generated charge which has previously been shown to affect the deposition of the drug and the function of an inhaler.
Keywords: Dry powder inhaler; Aerosol; Electrostatic charge; Spray dried lactose;

Rheological, mucoadhesive and release properties of Carbopol gels in hydrophilic cosolvents by Giulia Bonacucina; Sante Martelli; Giovanni F. Palmieri (115-130).
Carbopol is one of the most common thickening agent for water phases. It is used after neutralisation and its rheological properties in the aqueous medium are well known. The aim of this work was to investigate the gelation properties of Carbopol 971 e 974 polymeric systems in water-miscible cosolvents such as glycerine and PEG 400. Since in these cosolvents, carboxypolymethylene precipitates after neutralisation with a base, then the attention was pointed out of the gelation properties of the different systems at increasing temperature, in order to obtain Carbopols gels avoiding neutralisation and, at the same time, making possible the dissolution in these gels of insoluble or poorly soluble water drugs. Rheological properties of PEG 400 and glycerine samples were compared with similar systems in water by performing oscillatory analyses and measuring the main rheological parameters, G′, G″ and δ. The results obtained showed that Carbopol 971 and 974 in PEG 400 gave rise after heating to gels that show a satisfactory rheological behaviour. The elastic modulus is greater than the viscous one showing a remarkable elastic character of these samples and the performed frequency sweeps show a typical spectrum of a “gel-like” structure. Being Carbopols well-known mucoadhesive polymers, gels adhesive properties were studied using the ex vivo method. Then, the possible cutaneous irritation were also tested using the in vivo method (Draize test). No signs of cutaneous irritation and good mucoadhesive properties were obtained for the PEG 400 and water gels of Carbopol 974 prepared by heating.After rheological and mucoadhesive properties were set, paracetamol as a model drug was then inserted in the composition of the gels and the release characteristics were defined. Dissolution tests pointed out the greater release control properties of PEG 400-Carbopol 971 samples. These studies showed PEG 400-Carbopol systems as a first-rate alternative to traditional water gels.
Keywords: Gel; Rheology; Viscoelasticity; Mucoadhesion; Drug release;

The potential of a reverse water-in-fluorocarbon (w-in-FC) emulsion stabilized with a semifluorinated amphiphile, namely C8F17(CH2)11OP(O)[N(CH2CH2)2O]2 (F8H11DMP) for drug delivery through intrapulmonary administration was investigated in the mouse. This study involved assessment of the effect of single or repeated intranasal instillations of a plain emulsion on lung tissue integrity, and evaluation of blood glucose levels in mice treated with an insulin-loaded emulsion. When instilled intranasally to mice, the plain emulsion did not alter lung tissue integrity, as demonstrated by histological staining, and did not induce any airway inflammatory reaction. Treated mice exhibited decreased body weight within the 3–4 days that followed the first emulsion administration, but this decrease was reversible within few days. Mice instilled intranasally with the insulin-loaded emulsion displayed decreased blood glucose levels within the 20 min that followed the administration, thus demonstrating the potential of the reverse w-in-FC emulsion stabilized with F8H11DMP to systemically deliver drugs, including peptides, upon lung administration.
Keywords: Drug delivery; Lung; Reverse water-in-fluorocarbon emulsion; Fluorinated surfactant; Insulin;

Control of pulmonary absorption of water-soluble compounds by various viscous vehicles by Akira Yamamoto; Keigo Yamada; Hideaki Muramatsu; Asako Nishinaka; Shigeki Okumura; Naoki Okada; Takuya Fujita; Shozo Muranishi (141-149).
Effects of various viscous vehicles on the pulmonary absorption of water-soluble drugs were examined by an in situ pulmonary absorption experiment. Gelatin, polyvinylacohol (PVA), hydroxypropylcellose (HPC), chondroitin sulfate A sodium salt (CS), polyacrylic acid (PAA), methylcellulose #400 (MC400) and hyaluronic acid sodium salt (HA) were used as models of viscous vehicles. 5(6)-Carboxyfluorescein (CF) and fluorescein isothiocayanate-labeled dextran with an average molecular weight of 4000 (FD4) were used as water-soluble drugs. The plasma concentration of CF was controlled and regulated in the presence of these viscous vehicles, especially gelatin (1–5%) and polyvinyl alcohol (PVA) 1%. In the pharmacokinetic analysis, the C max values of CF significantly decreased, and its T max values increased in the presence of these viscous vehicles compared with the control. The MRT and MAT values of CF with these vehicles were significantly higher than those without these vehicles. Therefore, these findings indicated that the viscous vehicles were effective to regulate the absorption rate of CF. On the other hand, the pulmonary absorption of FD4 was not so much affected even in the presence of gelatin and PVA, although PVA slightly decreased MRT value, and significantly decreased T max value. Furthermore, we examined the release rate of CF from the cellulose tube containing various concentrations of gelatin. The release rate of CF from the cellulose tube with gelatin was inversely related to the viscosity of gelatin. In addition, the release rate of CF was inversely related to ΔMAT (ΔMAT = MATgel(MAT with gelatin)−MATsol(MAT without gelatin)) in the presence of varying concentrations of gelatin. These findings indicated that these viscous vehicles were effective to control the pulmonary absorption of CF, a water-soluble drug with low molecular weight and they might be useful to increase the local concentration of drugs in the lung.
Keywords: Pulmonary absorption; Gelatin; Viscosity; Excipient; Mucoadhesion; Controlled release;

Stability study of amorphous valdecoxib by Anshuman A. Ambike; K.R. Mahadik; Anant Paradkar (151-162).
Formulation of poorly water-soluble drugs in the most stable dosage form for oral delivery perhaps presents the greatest challenge to pharmaceutical industry. Physical transformation of drug substance into its more soluble but metastable amorphous form is one of the approaches for improving dissolution rate of such drugs. The present study utilizes technique of spray drying for preparation of solid dispersions (SDs) and includes stability study of the same. Valdecoxib (VLD), a prototype of poorly water-soluble drugs, has been the drug of choice. The hydrophilic carriers selected were polyvinylpyrrolidone K30 (PVP) and hydroxypropylcellulose (HPC). SDs and pure VLD in the form of spray dried powder (SDVLD) in comparison with pure drug and corresponding physical mixtures (PMs) were initially characterized and then subjected to stability testing at ambient temperature and relative humidity up to 3 months. During initial characterization, increase in saturation solubility and dissolution rate was observed in all samples. DSC and XRPD studies of SDVLD and SDs suggested generation of amorphous form of drug. IR spectroscopy revealed presence of hydrogen bonding in SDs. During stability testing, there was gradual decrease in saturation solubility and dissolution rate of SDs, over the period of 3 months. While, saturation solubility of SDVLD dropped drastically within 15 days and was almost comparable with pure VLD. SD PVP retained the amorphous form of drug throughout stability period, whereas SD HPC and SDVLD presented incidence of crystallinity after 1 month and 15 days, respectively. This was justified by enthalpy relaxation studies in which, amorphous VLD showed considerable relaxation of enthalpy at T g, while it was totally suppressed in SD PVP and partly in SD HPC. The study thus definitely reveals tremendous potential of solid dispersions of valdecoxib with PVP, from stability point of view.
Keywords: Valdecoxib; Amorphous; Solid dispersion; Stability study; Enthalpy relaxation;

The general belief that chemical structure determines the biological effect of drugs has led to several techniques to establish structure–activity relationships (SAR) that is useful in the development of more active compounds. Predicting toxic effects based on SAR, one can obtain toxicological data with a low cost–benefit ratio. Chlorophenols that represent a class of toxic agents frequently used in industrial processes are not satisfactorily described in the literature in relation to their toxicity. The main objective of this work is to relate the microbial activities of phenol, anisole and their chlorinated derivatives on Chromobacterium violaceum respiration with their physicochemical properties. Anisole and its chlorinated derivatives were used to evaluate the influence of phenol acidity on biological activity. The calculations were carried out at the semi-empirical AM1 and ab initio DFT levels employing the basis sets CEP-31G, CEP-31+Ge CEP-31G** that were parameterized using the continuum-solvation model COSMO for solvent contribution. Both empirical and theoretical properties were evaluated by chemometric analyses (hierarchical cluster analysis (HCA) and principal component analysis (PCA)), to correlate the physicochemical properties of the phenol, anisole and their chlorinated derivatives with their biological activities. The results obtained for the current work indicate that the biological activities of these compounds increase as the n-octanol/water (log  P) partition coefficients, ionization energies (IP), melting points (mp) and dissociation constants increase and the solvent effects (SE), enthalpies of formation (Δf H°) and proton affinities (PA) decrease.
Keywords: Inhibition effect; Phenol, anisole and their chlorinated derivatives; Chromobacterium violaceum respiration; Flow microcalorimetry; Theoretical method; Chemometric analysis; SAR;

The release profile of sodium dodecyl sulfate (SDS), a potent microbicide, from a female controlled drug delivery system (FcDDS) made of Carbopol 934P and hydroxypropyl methylcellulose (HPMC) was evaluated using a newly developed in vitro Simulant Vaginal System (SVS). The major parameters involved in the release profiles of SDS were categorized as: (1) formulation variables (total loading weight of intravaginal delivery systems, SDS loading doses in intravaginal delivery systems); (2) intrinsic variables (vaginal fluid secretion rate, vaginal fluid pH); and (3) extrinsic variables (inserting position). In most conditions, about 70% of the loading dose of SDS was released from FcDDS within 6 h of application. The release profile showed that concentrations needed for complete human papilloma virus (HPV) inactivation could be obtained within 10 min after the application. It was demonstrated that intrinsic variables (i.e., the rate and pH of vaginal fluid) played an integral role in determining the release profile of SDS, while loading dose of SDS in FcDDS did not significantly affect the percentage of the total amount of SDS released. It can be concluded that FcDDS can be exploited as a controlled delivery device for prevention against sexually transmitted diseases.
Keywords: Sodium dodecyl sulfate; Carbopol 934P; Female controlled drug delivery system; Vaginal fluid simulant; Release profile;

A direct flow injection analysis/mass spectrometry (FIA/MS) method was developed for the quantification of polyethylene glycol. The method was used for the evaluation of distribution uniformity and mixing homogeneity of polyethylene glycol 300 (PEG 300) as a component in drug formulation mixtures. In the method, five of the most intense ions of the PEG 300 oligomer were chosen for selected ion monitoring (SIM) by mass spectrometry. Standard calibration curves were established, using either single channel SIM or the summed intensity of all five SIM channels plotting against the standard concentrations. Both calibration approaches produced comparable results on quantification. The feasibility of the method was demonstrated using both atmospheric pressure chemical ionization (APCI) and electrospray ionization (ESI). The method provided fast and sensitive quantification of PEG 300 without tedious chromatographic separation or sample preparation. The method has been successfully adopted for the evaluation of the mixing process in drug formulations.
Keywords: PEG; Mass spectrometry; ESI; APCI;

Whilst contact angle measurements obtained using the Wilhelmy balance technique are accurate and reproducible for planar surfaces, their use for characterizing particulate materials is highly dependent upon accurate knowledge of the wet perimeter. This communication suggests that the approach of Pepin et al. [Int. J. Pharm. 152 (1997) 1] for wet perimeter determination using non-polar liquids may lead to erroneous conclusions. Alternative approaches for wet perimeter determination are suggested.
Keywords: Wilhelmy technique; Wet perimeter; Contact angle; Wettability;

Noticeboard (193-196).