International Journal of Pharmaceutics (v.228, #1-2)
UV absorption method should not be applied for determining amoxycillin in acidic dissolution test medium by Tadakazu Tokumura; Yoshiharu Machida (1-4).
In order to clarify the suitability of assay method, the stability of amoxycillin (AMX) in the acidic solution at pH 1.2 was determined by two different methods, ultraviolet absorption (UV) and HPLC methods. The determination was simultaneously performed for the same sample solutions. The data from HPLC method indicated that AMX degraded and the concentration of AMX in the acidic solution was decreased. The apparent first-order rate constant (k obs) for the degradation was 9.83×10−2 h−1, and the half-life was calculated to be 7.04 h. On the other hand, the data obtained from UV method apparently represented that the concentration of AMX increased with time-course. This phenomena was brought about by the increase of UV absorption at 272 nm, which accompanied with the degradation of AMX. These results clearly indicate that UV method can not be used for determining the samples accompanying the degradation of AMX. In general, the dissolution test (drug release test) has been used for the evaluation of a sustained-release dosage form of AMX. It is impossible to avoid the degradation of AMX in the test under acidic conditions. The results indicated that the UV method should not be used for the determination of AMX in the test.
Keywords: Amoxycillin; Determination method; Stability; Ultraviolet absorption method; Dissolution test; Acidic solution;
A critical review of the probable reasons for the poor variable bioavailability of rifampicin from anti-tubercular fixed-dose combination (FDC) products, and the likely solutions to the problem by Saranjit Singh; T.T Mariappan; R Shankar; N Sarda; Baljinder Singh (5-17).
The problem of poor/variable bioavailability of rifampicin, which is shown in particular when the drugs are present in anti-tubercular fixed-dose combination (FDC) products, is a matter of serious concern. There is a potential of failure of therapy in patients with an active disease. It perhaps also is a contributory factor towards the increasing resistance to anti-tubercular drugs. Unfortunately, the origin and cause of the problem is not clearly understood, though GMP and crystalline changes in the drug are invariably cited as the principal reasons. In this write-up, various probable physical and/or chemical reasons are critically reviewed. The enhanced decomposition of rifampicin in the presence of isoniazid in stomach after ingestion is indicated to be the key factor behind the problem. Some simple solutions offered by the knowledge of the cause are discussed and it is concluded that there is a need to have a multifaceted approach to handle the problem.
Keywords: Rifampicin; Isoniazid; Pyrazinamide; Ethambutol; FDC products; Bioavailability problem; Reasons; Solutions;
Production of griseofulvin nanoparticles using supercritical CO2 antisolvent with enhanced mass transfer by Pratibhash Chattopadhyay; Ram B. Gupta (19-31).
Griseofulvin (GF) is a poor water soluble, antifungal agent. The bioavailability of the drug and its absorption from the gastrointestinal tract can be greatly improved by particle size reduction. In this work, supercritical antisolvent precipitation with enhanced mass transfer (SAS-EM) has been proposed for the production of GF nanoparticles. SAS-EM is a modification of the currently existing supercritical antisolvent (SAS) precipitation technique and also utilizes supercritical CO2 as the antisolvent. In SAS-EM however, the solution jet is deflected by a surface vibrating at an ultrasonic frequency that atomizes the jet into small micro droplets. Further, the ultrasound field generated by the vibrating surface inside the supercritical media enhances mass transfer and prevents agglomeration due to increased mixing. GF nanoparticles of different sizes and morphologies have been obtained by varying the vibration intensity of the deflecting surface, which in turn is adjusted by changing the power supply to the attached ultrasound transducer. GF nanoparticles as low as 130 nm in size have been obtained corresponding to a power supply of 180 W. The effect of using different solvents on the size and morphology of the particles has also been studied.
Keywords: Griseofulvin; Supercritical CO2; Antisolvent; Ultrasound; Nanoparticles;
Controlled release of antifungal drug terbinafine hydrochloride from poly(N-vinyl 2-pyrrolidone/itaconic acid) hydrogels by Murat Şen; Arzu Yakar (33-41).
Adsorption and controlled release of terbinafine hydrochloride (TER-HCl) to and from pH-sensitive poly(N-vinyl 2-pyrrolidone/itaconic acid) P(VP/IA) hydrogels were investigated. P(VP/IA) hydrogels were prepared by irradiating the ternary monomer mixtures of N-vinyl 2-pyrrolidone/itaconic acid/ethylene glycol dimethacrylate in aqueous solution by γ-rays at ambient temperature. Hydrogels containing antifungal drug TER-HCl, at different drug-to-polymer ratios, were prepared by direct adsorption method. The influence of IA content in the gel on the adsorption capacities of hydrogels and the effect of pH on the releasing behavior of TER-HCl from the gel matrix were investigated. Terbinafine adsorption capacity of hydrogels was found to increase from 6 to 82 mg of TER-HCl per gram of dry gel with increasing drug concentration and amount of IA in the gel system. In-vitro drug-release studies in different buffer solutions showed that the basic parameters affecting the drug-release behavior of hydrogels are the pH of the solution and the IA content of the hydrogel.
Keywords: Terbinafine hydrochloride; Poly(N-vinyl 2 pyrrolidone/itaconic acid); Hydrogels; pH-sensitive;
Preparation and in vitro evaluation of liposomal/niosomal delivery systems for antipsoriatic drug dithranol by R Agarwal; O.P Katare; S.P Vyas (43-52).
Dithranol is one of the mainstays in the topical treatment of psoriasis. However, the use of dithranol in psoriatic condition is inconvenient and troublesome, as it has irritating, burning, staining and necrotizing effect on the normal as well as the diseased skin. The entrapment of drug in vesicles is viewed to help in the localized delivery of the drug and an improved availability of the drug at the site will reduce the dose and in turn, the dose-dependent side effects like irritation and staining. The investigations deal with critical parameters controlling the formulation and stabilization of dithranol loaded liposomes and niosomes. The entrapment efficiency of dithranol in liposomes was optimized by altering the proportion of phosphatidyl choline and cholesterol, and in case of niosomes it was between Span 60 and cholesterol. Hydration and permeation mediums were also established keeping in view the poor solubility and stability of dithranol. The mean liposome and niosomes sizes were 4±1.25 and 5±1.5 μm, respectively. The drug-leakage study carried out at different temperatures of 4–8, 25±2 and 37 °C for a period of two months affirms that the drug leakage increased at a higher temperature. The in vitro permeation study using mouse abdominal skin shows significantly enhanced permeation with vesicles as indicated by flux of dithranol from liposomes (23.13 μg/cm2/h) and niosomes (7.78 μg/cm2/h) as compared with the cream base (4.10 μg/cm2/h).
Keywords: Topical delivery; Liposomes; Niosomes; Dithranol; Entrapment efficiency; Stability; Skin-permeation;
Impaired bioavailability of rifampicin in presence of isoniazid from fixed dose combination (FDC) formulation by C.J Shishoo; S.A Shah; I.S Rathod; S.S Savale; M.J Vora (53-67).
The present study describes comparative bioavailability of rifampicin (RIF) after administration of a single component RIF (450 mg) capsule and rifampicin-isoniazid (RIF-INH) (450+300 mg) fixed dose combination (FDC) capsule formulations. Six healthy male volunteers participated in a single dose, two treatment, two period, cross-over study. A sensitive, specific and accurate HPTLC method was developed, validated and employed for estimation of RIF and its major active metabolite, 25-Desacetylrifampicin (25-DAR) levels, in urine. Using the urinary excretion data various pharmacokinetic parameters: AUC0–24, AUC0–∞, cumulative amount excreted in 24 h, peak excretion rate, etc. for both RIF and 25-DAR were calculated and compared statistically (ANOVA, 90% confidence interval for ratio). Significant decrease in the bioavailability (∼32% as RIF and ∼28% as 25-DAR) of RIF from FDC capsules was observed. The present bioavailability study confirms our serious doubts about the stability of RIF in presence of INH in acidic environment of stomach, which probably is the main factor responsible for the reduced bioavailability of RIF from RIF-INH combination formulations. This study underlines the fact that there is an urgent need to reconsider the formulation of the FDC product in order to minimize or avoid the decomposition of RIF in gastrointestinal tract.
Keywords: Rifampicin; Isoniazid; 25-Desacetylrifampicin; HPTLC; Fixed dose combination (FDC); Bioavailability; Urinary excretion;
In vitro study of low-frequency ultrasound-enhanced transdermal transport of fentanyl and caffeine across human and hairless rat skin by A Boucaud; L Machet; B Arbeille; M.C Machet; M Sournac; A Mavon; F Patat; L Vaillant (69-77).
The effect of low-frequency sonophoresis on fentanyl and caffeine permeation through human and hairless rat skin was studied in vitro. Experiments were performed using 20 kHz ultrasound applied at either continuous or discontinuous mode and with an average intensity of 2.5 W/cm2. The results showed that low-frequency ultrasound enhanced the transdermal transport of both fentanyl and caffeine across human and hairless rat skin. This was explained by both increasing flux during sonication and shortening the lag time. Discontinuous mode was found to be more effective in increasing transdermal penetration of fentanyl while transdermal transport of caffeine was enhanced by both continuous and pulsed mode. Histological and electron microscopy studies showed that human and hairless rat skin was unaffected by ultrasound exposure. Further studies will be necessary to determine the relative contribution of ultrasound parameters in low-frequency ultrasound-induced percutaneous enhancement of drug transport.
Keywords: Sonophoresis; Fentanyl; Caffeine; Transdermal delivery; Human skin; Hairless rat skin;
Evaluation of in vitro percutaneous absorption of lorazepam and clonazepam from hydro-alcoholic gel formulations by Carmelo Puglia; Francesco Bonina; Giuseppe Trapani; Massimo Franco; Maurizio Ricci (79-87).
Clonazepam and lorazepam are two anxiolytics, antidepressant agents, having suitable features for transdermal delivery. The objectives of this study were to evaluate the in vitro percutaneous absorption of these drugs through excised human skin (stratum corneum and epidermis, SCE) and to determine their in vitro permeation behavior from a series of hydro-alcoholic gel formulations containing various enhancing agents. The best permeation profile was obtained for both drugs applying them together with Azone in combination with propylene glycol (PG): these enhancers were able to increase the clonazepam and lorazepam percutaneous fluxes at steady-state about threefold, compared to the free enhancer formulations (Control). To explain the mechanism of the used promoters, the benzodiazepine diffusion and partitioning coefficients from the gel containing the enhancers were calculated. The results indicated that the Azone in combination with PG could act by increasing the benzodiazepine diffusion coefficients, Transcutol increased only the SC/vehicle partition coefficients, limonene in combination with PG appeared to increase both partition and diffusion coefficients moderately, while PG did not increase both the parameters. Furthermore, to evaluate the potential application of tested benzodiazepine formulations containing Azone in combination with PG using the flux values from the in vitro experiments, the corresponding steady-state plasma concentrations (C SS) were calculated. The obtained calculated C SS values are within the lorazepam therapeutic range and suggest that transdermal delivery of this drug could be regarded as feasible.
Keywords: Transdermal delivery; Lorazepam; Clonazepam; Penetration enhancers; In vitro;
Effect of melting point of chiral terpenes on human stratum corneum uptake by Kirsty M.B. Mackay; Adrian C. Williams; Brian W. Barry (89-97).
The effect of melting point of chiral penetration enhancers on their stratum corneum uptake was investigated. The pure enantiomers of a chiral compound often possess different melting points, and therefore dissimilar solubilities, to the racemate because of variations in their crystal structure. Two terpenes, menthol and neomenthol, saturated in propylene glycol/water, were applied to stratum corneum. Racemic menthol melts at ≈33 °C, some 9 °C lower than the pure enantiomers, whereas racemic neomenthol melts at 26 °C higher than the study temperature, considered as the theoretical melting point of its enantiomers, which are both liquids. Terpene solubility increased with the propylene glycol content of the vehicle. The lower melting forms of both penetration enhancers possessed the highest solubility in every vehicle. Maximum stratum corneum uptake was obtained from formulations containing the lower melting forms of each enhancer in 60% w/w propylene glycol systems (highest concentration used). Compared with menthol, the larger melting point difference between optical forms of neomenthol produced bigger differences in their uptake. Thus melting point depression of menthol and neomenthol, by selection of the appropriate optical form, increased the amount of terpene delivered to the stratum corneum, in agreement with theoretical predictions.
Keywords: Chiral enantiomers; Melting point; Penetration enhancers; Stratum corneum uptake; Terpenes;
The effect of surfactants on the skin penetration of diazepam by J. Shokri; A. Nokhodchi; A. Dashbolaghi; D. Hassan-Zadeh; T. Ghafourian; M. Barzegar Jalali (99-107).
The percutaneous permeation of diazepam was investigated in rat skin after application of a water–propylene glycol (50:50% v/v) using a diffusion cell technique. The effect of various surfactants (sodium lauryl sulfate (SLS), cetyltrimethylammonium bromide (CTAB), benzalkonium chloride or Tween 80) with different concentrations on skin permeability were evaluated. Flux, K p, lag time and enhancement ratios (ERs) of diazepam were measured over 10 h and compared with control sample (containing no surfactant). Furthermore, diazepam solubility in presence of surfactants was determined. The in vitro permeation experiments with rat skin revealed that the surfactant enhancers varied in their ability to enhance the flux of diazepam. Benzalkonium chloride which possessed the highest lipophilicity (log P=1.9) among cationic surfactants provided the greatest enhancement for diazepam flux (7.98-fold over control). CTAB (log P<1) at a concentration of 1% w/w exhibited no significant increase in flux of diazepam compared to control (1.16-fold over control). The results also showed that the highest ER was obtained in presence of 1% w/w surfactant with the exception of SLS and CTAB. The increase in flux at low enhancer concentrations is normally attributed to the ability of the surfactant molecules to penetrate the skin and increase its permeability. Reduction in the rate of transport of the drug present in enhancer systems beyond 1% w/w is attributed to the ability of the surfactant to form micelles and is normally observed only if interaction between micelle and the drug occurs. The results showed that the nature of enhancer greatly influences cutaneous barrier impairment.
Keywords: Skin absorption; Enhancer; Surfactants; Diazepam;
Physicochemical properties of microemulsion analogues of low density lipoprotein containing amphiphatic apoprotein B receptor sequences by M.D. Owens; G. Baillie; G.W. Halbert (109-117).
Low density lipoprotein (LDL) has been proposed as a drug targeting vector in cancer chemotherapy, however, research has been limited due to the necessity to isolate material from plasma. In this study, the physicochemical properties of synthetic lipid microemulsions containing an amphiphatic version of the apoprotein B receptor binding sequence have been examined. The effect of peptide sequence length, lipid anchor type and location along with microemulsion lipid composition were investigated via changes in particle size and zeta potential. Size increases were related to the amphiphatic peptides lipophilic portion and too a lesser extent by amino acid sequence length. Two lipophilic anchors, retinoic acid and cholesterol, produced large size increases whilst a single anchor (retinoic acid) did not affect size. The amphiphatic peptide reversed measured zeta potential from negative to positive values in a concentration dependent manner. This was related to peptide structure and could be effected by changes in pH, indicating that the peptide was surface located and responsive to the external environment. Alteration of microemulsion lipid composition also affected physicochemical properties but to a lesser degree than changes in the amphiphatic peptide. These novel systems may represent a useful synthetic alternative to native LDL for a variety of applications.
Keywords: LDL; Apoprotein B; Zeta potential; Size; Amphiphatic peptides; Drug targeting;
Preparation and in vitro evaluation of verapamil HCl and ibuprofen containing carrageenan beads by O. Sipahigil; B. Dortunç (119-128).
The objective of this study was to prepare and evaluate carrageenan beads as a controlled release system for a freely water soluble drug verapamil hydrochloride and a slightly water soluble drug ibuprofen. Beads were prepared by ionotropic gelation method. The influence of formulation factors (drug content, polymer concentration, counterion type and concentration, outer phase volume) on the particle size, encapsulation efficiency and in vitro release characteristics of beads was investigated. The encapsulation efficiency of veraparnil HCl in the beads (34.8–71.1%) was higher than that of ibuprofen (23.6–58%). While about 30% of ibuprofen was released at 6 h, about 70% of verapamil HCl was released in 5 h from the carrageenan beads prepared.
Keywords: Carrageenan; Beads; Verapamil HCl; Ibuprofen; Controlled release;
Macromolecular prodrugs. IX. Synthesis of polymer-fenoprofen conjugates by M Zovko; B Zorc; M Lovrek; B Boneschans (129-138).
Synthesis of several polymer-fenoprofen conjugates is described. Fenoprofen was first chemically modified into benzotriazolide 2 and amino acid amide derivatives: glycine fenoprofenamide (3a) and β-alanine fenoprofenamide (3b) and their benzotriazolides 6a and 6b. Compounds 2 and 6 readily reacted with polyhydroxy aspartamide-type polymers, i.e. poly[α,β-(N-2-hydroxyethyl-dl-aspartamide)] (PHEA) and poly[α,β-(N-3-hydroxypropyl-dl-aspartamide)] (PHPA) forming conjugates 5, 8a,b and 9a,b, respectively. Conjugate 11 was obtained by partial aminolysis of poly-dl-(2,5-dioxo-1,3-pyrrolidinediyl) (PSI) with 2-aminoethyl fenoprofenamide (3c), followed by total aminolysis with 2-hydroxyethylamine. The synthesised polymer-drug conjugates differed in type of covalent bounding, type and/or length of spacer and drug-loading.
Keywords: Fenoprofen; Polymer-drug conjugate; Macromolecular prodrug; Spacer; Poly[α,β-(N-2-hydroxyethyl-dl-aspartamide)]; Poly[α,β-(N-3-hydroxypropyl-dl-aspartamide)]; Poly[α,β-(N-2-aminoethyl-dl-aspartamide]-poly[α,β-(N-2-hydroxyethyl-dl-aspartamide)]-copolymer;
Micro-scale measurement of the mechanical properties of compressed pharmaceutical powders. 2: The dynamic moduli of microcrystalline cellulose by Bruno C. Hancock; Chad R. Dalton; Sophie-Dorothée Clas (139-145).
The use of two ‘micro-scale’ dynamic mechanical testing techniques for determining the viscoelastic properties of very small microcrystalline cellulose compacts (∼20 mg) is reported. The first method is a simple tensile ‘stretching’ test, and the second is a dynamic version of the three-point beam-bending technique. For both approaches the storage (elastic) and loss (viscous) moduli could be readily determined for compacts of a wide range of porosities. The experimentally determined storage moduli were consistently one order of magnitude greater than the corresponding loss moduli indicating a dominating elastic response for the microcrystalline cellulose compacts. The moduli determined using the oscillating three-point beam-bending technique were slightly lower than expected and this was attributed to sample anisotropy and imperfect sample alignment/friction during testing. The moduli obtained using the simple dynamic tension tests were practically identical to complex moduli values reported for much larger specimens, and it appears that this technique is well suited to measuring the dynamic mechanical properties of very small pharmaceutical powder compacts.
Keywords: Microcrystalline cellulose; Three-point beam-bending; Young's modulus; Dynamic mechanical spectrometer; Thermomechanical analyzer; Storage modulus; Loss modulus; Damping; Elasticity;
Heparin penetration into and permeation through human skin from aqueous and liposomal formulations in vitro by Gabriele Betz; Pegah Nowbakht; Roger Imboden; Georgios Imanidis (147-159).
The transport of unfractionated (UH) and low molecular weight Heparin (LMWH) in human skin was investigated in vitro using heat separated epidermal membrane and dermis and the effect of liposomal formulations with Phospholipon® 80 (PL80) and Sphingomyelin (SM) was assessed. The distribution of Heparin within skin tissue was studied by the tape stripping method. Heparin concentrations were measured with a biological assay. Transepidermal water loss was determined to characterize barrier properties of skin. No consistent permeation of Heparin through epidermal membrane was detected. Penetration into the epidermal membrane was for LMWH significantly greater than for UH. Accumulation of UH was largely restricted to the outermost layers of the stratum corneum while LMWH penetrated into deeper epidermal layers. UH penetration into epidermis was detected for the PL80 liposomal formulation only. The extent of LMWH penetration was independent of the formulation, LMWH, however, showed a trend to accumulate in deeper epidermal layers for the PL80 compared to the aqueous formulation. Thus, molecular weight and liposomal formulations influenced the penetration pattern of Heparin in the epidermis. It can not be concluded whether the concentration of LMWH achieved at the blood capillaries is sufficient to exert a pharmacological effect. UH permeated readily through dermis irrespectively of formulation and its accumulation in the dermis was significantly enhanced and its lag time of permeation increased in the presence of SM liposomes.
Keywords: Heparin sodium salt; Liposome; In vitro study; Percutaneous penetration; Tape-stripped skin;
Transdermal delivery of ketoprofen using microemulsions by Yun-Seok Rhee; Jung-Gyo Choi; Eun-Seok Park; Sang-Cheol Chi (161-170).
A transdermal preparation containing ketoprofen was developed using O/W microemulsion system. Of the oils tested, oleic acid was chosen as the oil phase of the microemulsion, as it showed a good solubilizing capacity and excellent skin permeation rate of the drug. Pseudoternary phase diagrams were constructed to obtain the concentration range of oil, surfactant and cosurfactant for microemulsion formation, and the effect of these additives on skin permeation of ketoprofen was evaluated with excised rat skins. The optimum formulation of the microemulsion consisted of 3% ketoprofen, 6% oleic acid, 30% Labrasol/Cremophor RH 40 (1:1) and water. Terpenes were added to the microemulsion at the level of 5% and their effect on the skin permeation of ketoprofen from the microemulsion was evaluated. Of the four terpenes used, only limonene resulted in a powerful enhancing activity (3-fold increase over control).
Keywords: Microemulsion; Ketoprofen; Enhancer; Transdermal delivery;
Modulation of P-glycoprotein activity in Calu-3 cells using steroids and β-ligands by Karen O Hamilton; Mehran A Yazdanian; Kenneth L Audus (171-179).
The purpose of this work was to investigate if P-glycoprotein (Pgp) efflux pump activity could be inhibited in the sub-bronchial epithelial cell line, Calu-3, by glucocorticosteroids and β-ligands. The Pgp modulation efficiency of each compound was determined by its ability to increase the accumulation of the Pgp substrate rhodamine 123 (Rh123) accumulation in these cells. Pgp inhibition was observed at ≥100 μM steroids and β-ligand. The modulation effectiveness of the β-ligands increased with increasing hydrophobicity (log P octanol/aqueous) whereas an obvious correlation was not obtained with the complete set of steroids tested. Steroidal Pgp substrates did not affect Rh123 accumulation (e.g. aldosterone, dexamethasone, 11β, 17α, 21-OH progesterone). In contrast, two hydrophobic non-Pgp steroidal substrates (testosterone and progesterone) displayed different effects on Rh123 accumulation, with progesterone being the more potent modulator. The most hydrophobic β-ligand, propranolol, a known Pgp substrate, gave the largest increase in Rh123 accumulation in this therapeutic class. The β-ligand modulation efficiency could also be correlated to Pgp structural recognition elements such as hydrogen bonding potential, the presence of a basic nitrogen and planar aromatic ring. No effect on Rh123 accumulation was observed with the formulation additives tested (ethanol, glycerol and palmitoyl carnitine) at concentrations previously reported to be non-toxic to Calu-3 cells.
Keywords: Calu-3; P-glycoprotein; Modulation; Steroids; β-ligands;
Optimized conditions of bio-mimetic artificial membrane permeation assay by Kiyohiko Sugano; Hirokazu Hamada; Minoru Machida; Hidetoshi Ushio; Kimitoshi Saitoh; Katsuhide Terada (181-188).
Effects of pH and co-solvents on the bio-mimetic artificial membrane permeation assay were investigated to determine the optimal conditions for the prediction of oral absorption. The permeability (P am) of 33 structurally diverse drugs to the PC/PE/PS/PI/CHO/1,7-octadiene membrane system (bio-mimetic lipid (BML) membrane) was measured at pH 5.5, 6.5, and 7.4. The pH dependence of P am was in accordance with the pH partition theory. The better prediction of oral absorption (fraction of a dose absorbed) was shown under the pH 5.5 condition (r=0.866, n=25) and/or pH 6.5 (r=0.865, n=28), rather than pH 7.4 (r=0.767, n=24). Then, the appropriate conditions for determining the permeability of poorly soluble compounds were examined. Dimethysulfoxide (DMSO), ethanol (EtOH) and polyoxyethyleneglycol 400 (PEG 400) were added up to 30% to the transport medium as solubilizers. DMSO, EtOH and PEG 400 decreased P am of hydrocortisone and propranolol. For example, DMSO (30%) decreased P am of hydrocortisone by 60% and by 70% in the case of propranolol. DMSO and PEG 400 also decreased P am of ketoprofen. In contrast, EtOH produced an opposite effect on permeability, i.e. an increased P am of ketoprofen. Therefore, the high concentration of these co-solvents could lead to the under- or overestimation of drug permeability.
Keywords: Permeability; pH; DMSO; EtOH; PEG; Intestinal absorption;
Factors influencing drug release from stearic acid based compacts by Bronagh U. Killen; Owen I. Corrigan (189-198).
Fatty acids are potentially suitable carriers for use in the design of drug delivery systems, being biocompatible, biodegradable inexpensive and of low toxicity. The release of the model compound benzoic acid from fatty acid compacts of stearic acid was evaluated using the USP Apparatus 2 dissolution assembly in phosphate buffer pH 7.4. Matrix controlled drug release was expected. Release profiles were approximated by square root of time kinetics. Release rate was independent of stirring speed in the rpm range 50–150, however, at 200 rpm a significant increase in release rate was observed particularly at later times, the amount released versus square root of time plots becoming non-linear. Release was independent of compression pressure in the range 1–7 tons. The particle size of the benzoic acid and stearic acid used had a significant influence on release. The use of particles in the range 250–500 μm gave release rate constants (k, g/cm2 per min0.5) ∼1.5 greater than those of smaller particle size (63–125 μm). The formation factor (F) tended to increase exponentially with drug loading, the increase being steeper for compacts prepared from the larger particle sizes. At 80% drug loading for large sized systems the matrix appeared to offer little resistance to drug release and F approached one.
Keywords: Fatty acid carriers; Stearic acid; Benzoic acid; Release mechanism;
Determination of partial solubility parameters of five benzodiazepines in individual solvents by S. Verheyen; P. Augustijns; R. Kinget; G. Van den Mooter (199-207).
Three and four component partial solubility parameters for diazepam, lorazepam, oxazepam, prazepam and temazepam were determined using the extended and expanded Hansen regression models. A comparison was made also with solubility parameters calculated by the group contribution method proposed by Van Krevelen. Although a limited number of solvents was used, the results from the present study indicate that the partial solubility parameters obtained from the experimental regression models clearly reflect the structural differences in these five structurally related molecules. High R 2-values were observed in the regression models (0.932≤R 2≤0.984), except for lorazepam (0.606≤R 2≤0.825). This was attributed to difficulties in obtaining reliable values of the temperature and heat of fusion due to thermal decomposition of this compound. Introduction of the Flory–Huggins size correction parameter did not improve the R 2- and F-values in any of the regression models used.
Keywords: Partial solubility parameters; Benzodiazepines; Solubility; Group contribution method;
Evaluation of the mechanical destructive force in the stomach of dog by Masaharu Kamba; Yasuo Seta; Akira Kusai; Kenji Nishimura (209-217).
Orally administered dosage forms receive a destructive force in the gastrointestinal (GI) tract due to peristalsis. In this study, the destructive force was measured with a ‘destructive force-dependent release system’ (DDRS). DDRS is a press-coated tablet with an extremely brittle outer layer composed of highly hydrophobic Teflon® powder, which is molded with a weak compression force. Teflon® powder forms a porous but water-impermeable layer around the core tablet. A marker drug contained in the core tablet is released only when the tablet receives a force larger than its pre-determined crushing strength. A comparison of the physiological conditions in the GI tract of dogs with those of humans, including the destructive force against tablets in the stomach, helps us to understand their difference in bioavailability of oral dosage forms. With DDRS, it is possible to evaluate the destructive force of both human and dog stomach using the same method. Therefore, the destructive force data from human and dog can be directly compared. The destructive force in the dog stomach was evaluated to be 3.2 N, which was considerably stronger than that of humans.
Keywords: Stomach; Destructive force; Teflon; Gastrointestinal transit; Dog;
Resistivities of placebo and active Diskus® inhalers compared by Mariëlle E.A.C Broeders; Johan Molema; Hans Th.M Folgering (219-222).
Objective: Verbal instruction and demonstration of inhalation technique are essential to enhance the effectiveness of inhalation therapy. Placebo devices are commonly used to instruct patients. It is not obvious that patients, who inhale with an adequate flow through an empty placebo Diskus®, would also be able to do so with active inhalers containing a strip with powder. The presence of powder may result in a change in resistivity. We compared the resistivities of a placebo Diskus® being empty; a powder filled Diskus® inhaler and a Diskus® inhaler with an empty blister. Methods: A Diskus® inhaler was placed in a box, which enabled measurement of pressure drop and flow rates. Ten placebo and ten Ventolin® Diskus® inhalers were measured. Twelve pressure- and flow-profiles were recorded through each device. After each simulated inhalation through a powder filled blister, a second inhalation was performed through the empty blister. The resistivity was calculated by pressure-flow equation. Results: The resistivity of the empty placebo Diskus® inhaler was slightly but significantly higher than both blister filled inhalers, with or without powder (0.0215 vs. 0.0211 and 0.0211 (kPa)0.5 (l min−1)−1) (P<0.001). Conclusion: Patients who are capable of generating sufficient flow through a placebo Diskus® will surely be capable of generating equivalent flows through a Diskus® inhaler containing a strip with active drug substance.
Keywords: Inhalation therapy; Instruction; Diskus® inhaler; Resistivity;
Transport Processes in Pharmaceutical Systems by Ian Kellaway (223).