International Journal of Pharmaceutics (v.222, #1)

In vivo evaluation of hydrochlorothiazide liquisolid tablets in beagle dogs by Khaled A. Khaled; Yousif A. Asiri; Yousry M. El-Sayed (1-6).
This study was carried out to evaluate the absorption characteristics of experimentally developed hydrochlorothiazide liquisolid tablets using six male beagle dogs. Comparison with reference commercial tablets was made. As no bibliographic data were found for the pharmacokinetic parameters of the drug in dogs, an intravenous drug administration was included in the study. The drug was administered orally as a single 25 mg dose of commercial and liquisolid tablets on two occasions in a randomized two-way crossover design. The pharmacokinetic parameters of the drug post intravenous dosing were reported for the first time. The results of the oral administration revealed statistically significant differences between the liquisolid and the commercial tablets in the area under the plasma concentration–time curve, the peak plasma concentration, and the absolute bioavailability. On the other hand, no significant differences were observed between the two formulations with regard to the mean residence time, the mean absorption time, and the rate of absorption. The absolute bioavailability of the drug from the liquisolid tablets was 15% higher than that from the commercial one. The parametric 90% confidence intervals for the different parameters were higher than the commonly expected intervals for bioequivalency, indicating greater bioavailability of the liquisolid tablets.
Keywords: Hydrochlorothiazide; Liquisolid tablets; Bioavailability; Pharmacokinetic;

The kinetics of water penetration and molsidomine release from both hydroxypropylmethyl cellulose (HPMC) and mixed HPMC/thermally pregelatinized waxy maize starch (SDWMT) hydrophilic matrices has been examined in 0.1 mol dm−3 HCl (pH 1.0) and 0.06 mol dm−3 Na3PO4/HCl buffer (pH 6.8). The rheological oscillatory test parameters of their gel layers obtained by swelling of the matrices in the two aqueous media have been observed. The kinetic swelling properties of mixed HPMC/SDWMT hydrogels (i.e. degree and velocity of both water penetration and swelling, transport mechanism which controls solvent sorption) directly influence the drug release behaviour and the structural features of the formed gel layer. Both diffusion processes are diffusion-controlled ones, their mechanisms being influenced insignificantly by the relaxation properties of the hydrated macromolecules. It has been established by means of comparative viscoelastic analysis, that mixed HPMC/SDWMT hydrogels demonstrate the typical behaviour of ‘filled’ composite systems having poor adhesion between the surface of the elastic SDWMT ‘filler’ and the continuous HPMC phase. Due to the inter-phase relations between the swollen starch granules and the linear cellulose derivative as well as to the specific structure of amylopectin molecule, the pregelatinized waxy maize starch shows a stronger influence on the velocities of both water penetration and drug release from mixed HPMC/SDWMT matrices.
Keywords: Thermally pregelatinized waxy maize starch; Hydroxypropylmethyl cellulose; Mixed hydrophilic matrices; Water penetration; Rheology;

Microspheres were prepared from poly(L-lactic acid) polymers having molecular weights between 500 and 50k g/mol. The polymers were synthesized using two initiator molecules, L-lactic acid oligomer (PLLA-LA) or stearyl alcohol (PLLA-SA). For both PLLA-LA and PLLA-SA polymers, glass (Tg) and melting (Tm) transition temperatures and enthalpy of melting all increased as the polymer molecular weight increased. PLLA-SA showed the greatest change in Tg (−13 to 54°C) as molecular weight increased from 500 to 10k g/mol, compared to 25 to 55°C for PLLA-LA polymers. Changes in Tm and enthalpy of melting with increasing molecular weight were similar for both PLLA-LA and PLLA-SA. Paclitaxel release from 30% paclitaxel loaded microspheres in the size range of 50–90 μm was affected by these changes in polymer properties as molecular weight increased. As the molecular weight increased from 2k to 50k g/mol the amount of drug released from microspheres over 14 days decreased from 76 to 11% of the initial drug load. The release profiles were consistent with a diffusion controlled mechanism provided a two-compartment model was employed. According to this model, the total amount of ‘available’ drug (compartment 1) was released by diffusion in 14 days while the remainder (compartment 2) was confined within the polymeric matrix and could not diffuse out at a measurable rate. Following the in vitro release study, microsphere made from 2k–10k g/mol polymers showed significant signs of disintegration whereas 50k g/mol polymer microspheres remained intact.

The melting point of lidocaine was significantly lowered when mixed with thymol and/or aqueous ethanol. Mixtures of lidocaine and thymol at ratios within the range of 30:70–70:30 (w:w) became homogeneous oils at 25°C. In a pH 9.2 carbonate buffer containing 25% ethanol, lidocaine (5%, w:w) also liquefied at 25°C. The studies led to the development of novel two-phase melt systems of lidocaine (TMS) which consisted of a highly concentrated oil phase of lidocaine and an alcoholic aqueous phase. A compositional phase diagram showed that in aqueous dispersions of lidocaine, concurrent use of thymol and ethanol depressed the melting point of lidocaine more effectively than when they were used individually. Both thymol and aqueous ethanol were necessary as melting point depressing agents to achieve the highest possible lidocaine concentration of 87% (w:w) in the oil phase of a TMS at 25°C. Containing an internal oil phase and an external aqueous phase at ambient temperature, such a TMS can be readily formulated into topical O/W cream after addition of proper surfactants and thickening agents. In an anesthetic activity test using mouse tail-flick model, a 5% lidocaine cream prepared was highly effective as shown by the prolonged latency time of the mice to a heat stimulus as compared with a placebo (P<0.05).
Keywords: Lidocaine; Thymol; Melting point depression; Dermal anesthesia; Two-phase melt systems;

Topical formulations of piroxicam were evaluated by determination of their in vitro release and in vivo anti-inflammatory effect. The in vitro release assay demonstrated that the microemulsion (ME) systems provided a reservoir effect for piroxicam release. However, the incorporation of the ME into carboxyvinilic gel provoked a greater reduction in the release of piroxicam than the ME system alone. Anti-inflammatory activity was carried out by the cotton pellet granuloma inhibition bioassay. Topical anti-inflammatory effect of the piroxicam inclusion complex/ME contained in carboxyvinilic gel showed significant inhibition of the inflammation process (36.9%, P<0.05). Subcutaneous administration of the drug formulations showed a significant effect on the inhibition of inflammation, 68.8 and 70.5%, P<0.05, when the piroxicam was incorporated in ME and in the combined system β-cyclodextrin (β-CD)/ME, respectively, relative to the buffered piroxicam (42.2%). These results demonstrated that the ME induced prolonged effects, providing inhibition of the inflammation for 9 days after a single dose administration.
Keywords: Piroxicam; β-Cyclodextrin; Microemulsion; Anti-inflammatory effect; In vitro drug release;

The effects of hydrogenated and unhydrogenated phosphatidylcholine (HPC, PC) on the permeation of indomethacin (IM) through hairless rat skin were investigated using liquid paraffin (LP) and a gel prepared with LP and hydrogenated soybean phospholipid (HSL). IM solubility at 95°C increased in proportion to the concentration of HPC or PC, whereas solubility at 37°C did not increase with HPC. IM showed no permeation until 10 h from LP without HPC/PC, but permeated at rates of ≈5 and 10 μg/cm2 within 10 h from LP with HPC and PC, respectively. The permeation from the gel with various formulations (HSL, 15%; PC/HPC, 0–5%; IM, 0.5–2%) was determined. Permeation rates were 1.7–4.8 μg/cm2 per h and were proportional to the skin concentration. Skin concentration was correlated to the release rate from the gel. We concluded that IM was solubilized by phospholipids, high activity in the vehicle led to high partition of IM in skin, and permeation increased due to a high skin concentration.
Keywords: Skin permeation; Phosphatidylcholine; Indomethacin; Oily gel; Hairless rat skin;

The purpose of this study was to investigate whether the deformation and densification during compression of one type of granules are affected by adjacent granules of a different porosity, corresponding to different mechanical strength. Three mixtures were prepared, each consisting of two types of microcrystalline cellulose pellets (intermediate porosity study pellets plus low, intermediate or high porosity surrounding pellets) in the proportion 1:7. The mixtures were compressed and the study pellets were retrieved and analysed in terms of porosity, thickness, surface area and shape. It was shown that the study pellets were compressed by deformation and densification. The degree of densification (decrease in porosity) of the study pellets was independent of the porosity of the surrounding pellets but the deformability (changes in the thickness, surface area and shape) of the study pellets was linked with the porosity of the surrounding pellets. It is concluded that the mode of deformation of the study pellets was regulated by the porosity of the surrounding granules; in a mixture containing granules with a low porosity, compression resulted in irregular study granules with regularly positioned indentations caused by the surrounding granules. The compression properties of the surrounding granules affected the flattening of the study granules to a lesser degree.
Keywords: Microcrystalline cellulose; Extrusion/spheronisation; Intragranular porosity; Deformation; Densification; Mode of deformation;

Permeability of lipophilic compounds in drug discovery using in-vitro human absorption model, Caco-2 by Gopal Krishna; Kwang-jong Chen; Chin-chung Lin; Amin A Nomeir (77-89).
Highly lipophilic compounds are often encountered in the early stages of drug discovery. The apparent permeability (Papp) of these compounds in Caco-2 cell could be underestimated because of considerable retention by the Caco-2 monolayer and non-specific binding to transwell surface. We have utilized a general approach for the determination of permeability of these compounds, which includes the addition of 1–5% DMSO in the apical (AP) and 4% bovine serum albumin (BSA) in the basolateral (BA) side. Two highly lipophilic and highly protein bound Schering compounds, SCH-A and SCH-B, exhibited poor recovery and low Papp in the conventional Caco-2 system that included 1% DMSO in the AP and BA sides. In contrast, both compounds were well absorbed in cynomolgus monkeys. Inclusion of BSA (up to 4%) in the BA side provided necessary absorptive driving force similar to in vivo sink conditions improving both recovery and Papp of these compounds as well as progesterone, a model highly lipophilic and highly protein bound compound. Whereas, the recovery and Papp of mannitol (high recovery, low permeability) and propranolol (high recovery, high permeability) remained unaffected. The presence of 4% BSA increased Papp of SCH-A, SCH-B, and progesterone by five-, four-, and three-fold, respectively. We also compared this approach with a second, based on the disappearance of the compound from the AP side, which resulted in a reasonable estimate of the permeability (23.3×10−6 cm/s) for SCH-A. The results demonstrated that the reliable estimates of permeability of highly lipophilic compounds that are subjected to considerable retention by the cell monolayer and exhibit non-specific binding are obtained by the addition of BSA to the BA side.
Keywords: Caco-2; Bovine serum albumin; Non-specific binding; Permeability; Oral absorption; Lipophilic compounds;

Stabilization of minodronic acid in aqueous solution for parenteral formulation by Katsutoshi Nakamura; Tomonari Tanaka; Katsumi Saito; Shigeharu Yokohama; Takashi Sonobe (91-99).
The composition, concentration, and buffer pH of potential minodronic acid formulations were evaluated for their drug stability and for their tendency to generate particles after storage for up to 4 weeks at 60°C. The results indicate that citrate and tartrate buffers maintain drug stability and inhibit the formation of particles. The stability of minodronic acid in these solutions increased slightly as the buffer concentration increased, exhibiting less particle formation than in other buffers. Since citrate buffer was considered the most promising stabilizer for minodronic acid, the pH-stability relationship in 100 mM citrate with pH ranging from 3 to 7 was evaluated during storage for 4 weeks at 60°C. The results demonstrate that solution pH of 3–5 result in optimal stability of minodronic acid with no formation of precipitates. A white precipitate was observed in citrate-containing sample solutions with pH of 6 and 7. Analysis of the isolated precipitate provided support for the hypothesis that the precipitate is a complex between minodronic acid and aluminum ions apparently leached from the glass of the ampoules.
Keywords: Minodronic acid; Parenteral formulation; Stability; Precipitate; Complex; Aluminum ion;

Delivery of HFA and CFC salbutamol from spacer devices used in infancy by Jean-Christophe Dubus; Rodney Rhem; Myrna Dolovich (101-108).
The aim of the study was to compare the in vitro delivery of four salbutamol pressurized metered-dose inhalers (pMDIs) via the three spacer devices commonly used in European infants: Aerochamber-Infant®, Babyhaler®, and metallic NES-spacer®. Emitted dose (ED) and fine particle dose (FPD, particles<5.8 μm) of each combination of spacer device and pMDI (chlorofluorocarbon-based Ventoline®, Eolène®, Spréor®, and hydrofluoroalkane-based Airomir®) were measured respectively using unit dose sampling tubes (n=30 per combination) and an 8-stage cascade impactor (n=6 per group). The results were compared by analysis of variance and the Student–Newman–Keuls method. ED of Airomir® was always greater than for Ventoline® (P<0.05). FPD obtained with Ventoline® was the lowest, with Eolène®>Airomir®=Spréor®>Ventoline® (P<0.05). Only Airomir® produced a similar FPD with all three spacer devices. Chlorofluorocarbon-salbutamol pMDIs are not generics when used with spacer devices. The three spacer devices may be used interchangeably with Airomir®.
Keywords: Chlorofluorocarbon; Hydrofluoroalkane; Inhaled therapy; Pressurized metered-dose inhaler; Salbutamol; Spacer devices;

This paper investigates the effect of starch microspheres on the absorption enhancing efficiency of various enhancer systems in formulations with insulin after application in the nasal cavity of sheep. The enhancers studied were lysophosphatidylcholine, glycodeoxycholate and sodium taurodihydroxyfusidate, a bile salt derivative. The enhancers were selected on the basis of their perceived or proven mechanism of action and worked predominantly by interacting with the lipid membrane. The bioadhesive starch microspheres were shown to increase synergistically the effect of the absorption enhancers on the transport of the insulin across the nasal membrane. Dependent on the potency of the enhancer system the increment in absorption enhancement was shown to be from 1.4 times to 5 times that obtained for the absorption enhancer in solution.
Keywords: Lysophosphatidylcholine; Glycodeoxycholate; Sodium taurodihydroxyfusidate; Starch microspheres; Nasal delivery; Absorption enhancers;

A TSM sensor investigation of low crystallinity cellulose films by Matthew Reason; Paul Teesdale-Spittle; Roger Latham; Gordon Dawson; P. Porteous; Geoff Smith (121-128).
A thickness shear mode (TSM) quartz sensor has been used to characterize the substantivity, viscoelasticity, and mucoadhesive properties of low crystallinity cellulose (LCC) films. LCC is a novel pharmaceutical excipient that has been attributed with mucoadhesive properties. Thin films of LCC were deposited onto TSM sensors by a spin coating technique. The films were treated by passing water or 1.0% w/v mucin solution (pH 3.7 or 7.0) over the surface. Changes in the mass and viscosity of the film were observed by monitoring changes in the impedance spectra of the coated TSM sensors. Scanning electron micrographs (SEMs) of each film were used to assist the interpretation of the TSM sensor data. This study showed that LCC forms highly tenacious and viscoelastic films able to withstand prolonged (approximately 1 h) exposure to both water and mucin solution. Furthermore, these results indicate that the films may have mucoadhesive properties as LCC was found to bind significant (P<0.05) amounts of mucin in comparison with control measurements. Mucin binding to the LCC sensor was greater at pH 3.7 (P<0.05) than at pH 7.0, suggesting that the LCC formulation is mucoadhesive under these conditions.
Keywords: Thickness shear mode sensor; Low crystallinity cellulose; Mucoadhesion; Quartz crystal microbalance;

The purpose of this study was to apply the attractive technique of the supercritical fluid to the preparation of solvent-free solid dispersions. In particular, the gas antisolvent crystallisation technique (GAS), using supercritical carbon dioxide as processing medium, has been considered to prepare an enhanced release dosage form for of the poorly soluble carbamazepine, employing PEG 4000 as a hydrophilic carrier. The physical characterisation of the systems using laser granulometer, powder X-ray diffraction, thermal analyses, and scanning electron microscopy was carried out in order to understand the influence of this technological process on the physical status of the drug. The results of the physical characterisation attested a substantial correspondence of the solid state of the drug before and after treatment with GAS technique, whereas a pronounced change in size and morphology of the drug crystals was noticed. The dramatic reduction of the dimensions and the better crystal shape, together with the presence of the hydrophilic polymer determined a remarkable enhancement of the in vitro drug dissolution rate.
Keywords: Gas antisolvent crystallisation; Supercritical fluids; Solid dispersions; Carbamazepine; PEG 4000; Physico-chemical characterisation;

Solid dispersions were prepared with the extremely poorly water soluble drug, probucol and the water soluble polymers, polyvinyl pyrrolidone (PVP), polyacrylic acid (PAA) or polyethylene oxide (PEO) and blends of these polymers. The solid dispersions were prepared either by the solvent evaporation method, or by compression moulding into films. The materials were characterised by a combination of thermal analysis and FT-Raman spectroscopy. The physical state of the drug was observed to be dependent on the carrier, thus the PVP solid dispersions contained amorphous probucol, whilst the PAA and PEO systems contained the crystalline polymorph II. The method of production was not found to greatly influence the state of the drug in the solid dispersion. The greatest extent of release into solution was observed for the binary blend of drug and PEO, and the blending of polymers was not found to have any advantageous effects in this study.
Keywords: Probucol; Solid dispersion; Polymer; Crystalline; Amorphous;

Stripping method to quantify absorption of two sunscreens in human by C. Couteau; N. Perez Cullel; A.E. Connan; L.J.M. Coiffard (153-157).
With the aim to know the remanence of two sunscreens, PEG-25 PABA and benzophenone, two cases have been considered: the application of aqueous solution of two filters studied for the application of oil-in-water (O/W) emulsions containing the same two filters on the skin of 21 voluntary women. In order to determine the quantity of filter remaining in the stratum corneum after times of application, which vary from 1 to 7 h, a series of six strippings have been carried out. The sunscreen agents were assessed by HPLC. With this study, it has been possible to emphasize the best remanence of benzophenone 4. Moreover, the incorporation of photo-protective agents in a O/W emulsion promotes their penetration, and this is particularly due to benzophenone 4.
Keywords: Benzophenone 4; PEG-25 PABA; Penetration; Remanence; Stripping;

Notice board (159-162).

Contents (163-167).