International Journal of Pharmaceutics (v.272, #1-2)
Editorial Board (iii).
Solid dispersion of carbamazepine in PVP K30 by conventional solvent evaporation and supercritical methods by S Sethia; E Squillante (1-10).
This study compares the physicochemical properties of carbamazepine (CBZ) solid dispersions prepared by either a conventional solvent evaporation versus a supercritical fluid process. Solid dispersions of carbamazepine in polyvinylpyrrolidone (PVP) K30 with either Gelucire 44/14 or Vitamin E TPGS, NF (d-α-tocopheryl polyethylene glycol 1000 succinate) were prepared and characterized by intrinsic dissolution, differential scanning calorimetry, powder X-ray diffraction and Fourier transform infrared spectroscopy. CBZ/PVP K30 and CBZ/PVP K30/TPGS solid dispersions showed increased dissolution rate. The best intrinsic dissolution rate (IDR) was obtained for supercritically processed CBZ/PVP K30 that was four-fold higher than pure CBZ. Thermograms of various solid dispersions did not show the melting peak of CBZ, indicating that CBZ was in amorphous form inside the carrier system. This was further confirmed by X-ray diffraction studies. Infrared spectroscopic studies showed interaction between CBZ and PVP K30 in solid dispersions. The amorphous state of CBZ coupled with presence of interaction between drug and PVP K30 suggests fewer, if any, stability problems. Because the supercritical-based process produced solid dispersions with IDR better than conventional solid dispersions augmented with amphiphilic carriers, stability issues associated with lipid carriers do not apply, which, in turn, implies easier scale up under current Good Manufacturing Practice for this technique.
Keywords: Supercritical fluid; TPGS; PVP K30; Carbamazepine; Amorphous; Solid dispersions;
Evaluation of carboxymethyl guar films for the formulation of transdermal therapeutic systems by S. Narasimha Murthy; Shobha Rani R. Hiremath; K.L.K. Paranjothy (11-18).
Carboxymethyl guar (CMGS), an anionic semisynthetic guar gum derivative was evaluated for its suitability of use in transdermal drug-delivery systems. Terbutaline sulfate (TS) was used as a model drug. The diffusion of terbutaline sulfate from CMGS solution was relatively slower at pH 5 than at pH 10. It is most likely that the interaction between CMGS and terbutaline sulfate at pH 5 is physical, involving static interaction. The ability of such interactions in modifying the release kinetics of drug from the CMGS transdermal films was studied. The release was exponential from pH 5 formulations whereas the release rate followed zero or Higuchian order from pH 10 formulations. However, the diffusion kinetics of both pH 5 and pH 10 formulations followed zero order across human cadaver epidermis. Such an interaction was also found to alter the pharmacokinetic parameters of the drug. The steady-state concentration of TS was relatively consistent and the bioavailability was ∼50% higher in pH 5 formulations than pH 10. The elimination rate constant/half-life was significantly different between pH 5 and pH 10 formulations.
Keywords: Carboxymethyl guar; Terbutaline sulfate; Transdermal delivery;
Sustained release of acetaminophen from a heterogeneous mixture of two hydrophilic non-ionic cellulose ether polymers by Nkere K. Ebube; Alan B. Jones (19-27).
This study examined the release of acetaminophen (APAP) from hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) matrices. The effect of pseudoephedrine (PE) as a co-active, HPMC:HPC ratio, polymer loading, pH of the dissolution media, and compression force on APAP release were studied. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and HPC were compressed into tablets at different compression forces. APAP release from the matrix tablets was not considerably influenced by changes in HPMC:HPC ratio or compression force. The rate of drug release was significantly affected by pH of the dissolution media, total polymer loading, and the presence of PE. Drug release from the formulations containing both APAP and PE was slower than those containing only APAP. Drug release from tablets formulated with APAP only showed an initial burst at pH 1.16 or 7.45. Formulations containing both APAP and PE showed slower drug release at pH 1.16 than at pH 7.4. The drug release data showed a good fit to the Power Law Model. The mechanism of drug release is consistent with a complex behavior. The results of the tablet erosion studies indicated that the amount of APAP released was linearly related to the percentage of tablet weight loss. The kinetics of tablet water uptake was consistent with a diffusion and stress relaxation mechanism.
Keywords: Acetaminophen; Sustained release; Heterogeneous hydrophilic matrix; Pseudoephedrine;
The effect of solubilization on the oral bioavailability of three benzimidazole carbamate drugs by K Daniel-Mwambete; Susana Torrado; C Cuesta-Bandera; F Ponce-Gordo; J.J Torrado (29-36).
The effect of solubilization by complexation with povidone on the oral bioavailability of three anthelmintic benzimidazole carbamate drugs: mebendazole (MBZ), albendazole (ABZ) and ricobendazole (RBZ), was studied in mice. The following in vitro characteristics of the initial raw materials and the drug–povidone complexes were evaluated: melting point (MP); mean dissolution time (MDT); solubility constants (Cs) in n-octanol, acid (pH 1.2) and neutral (pH 7.4) aqueous media; apparent partition coefficients (P) and capacity factors (k w′) determined by HPLC. The following in vivo parameters were also evaluated: AUC0–∞, C max, T max and MRT. The possible relationship between in vitro characteristics and in vivo parameters was explored and it was found that an increase in solubility, especially in acidic medium, leads to an increase in AUC and C max and a decrease in T max. Therefore, dissolution seems to be the absorption limiting step for these drugs. For the in vivo parameters related to the amount of absorbed drug (AUC and C max), the best correlation was obtained with the in vitro characteristics related to solubility which are Cs, MP and MDT. On the other hand, there were good linear correlations between T max which is an in vivo parameter related to the rate of drug absorption, and the lipophilia/hydrophilia (log P and log k w′) relation-parameters.
Keywords: Solubility; Complexation; Povidone; Bioavailability; Solid dispersion;
Intranasal administration of melatonin starch microspheres by Shirui Mao; Jianming Chen; Zhenping Wei; Huan Liu; Dianzhou Bi (37-43).
Using melatonin as model drug, starch microspheres for intranasal administration were prepared by an emulsification-crosslinking technique using a uniform design to optimize preparation conditions. The entrapment ratio of melatonin in the microspheres was 11.0% and particle sizes ranged from 30 to 60 μm. Melatonin was released from the microspheres in a sustained manner in vitro. Nasal clearance of 99m Tc labeled starch microspheres was investigated using gamma scintigraphy. It was revealed that >80% of the starch microspheres could be detected in the nasal tissue 2 h after administration, compared to 30% for a solution. The pharmacokinetics of melatonin starch microspheres was investigated after intranasal administration. The absorption rate was rapid (T max=7.8 min), and the absolute bioavailability was high, 84.07%. A good correlation was found between in vitro release and in vivo absorption data.
Keywords: Melatonin; Starch microspheres; Intranasal administration;
Influence of encapsulation on the in vitro percutaneous absorption of octyl methoxycinnamate by M.M Jiménez; J Pelletier; M.F Bobin; M.C Martini (45-55).
The purpose of this study was to evaluate the in vitro transdermal permeation and skin accumulation of one ultraviolet (UV) absorber—octyl methoxycinnamate (OMC)—through pig skin and to determine the quantity of OMC in the skin surface and different pig skin layers (stratum corneum, viable epidermis, dermis, and receptor fluid). Four cases have been considered: the application of oil-in-water (O/W) and water-in-oil (W/O) emulsions containing the same filter free and encapsulated in nanocapsules (NC). The influence of the carrier on the percutaneous penetration was studied.Data showed that UV absorber exhibited increases in skin accumulation when is formulated in emulsions in free form. Skin accumulation of OMC-free in the emulsions was significantly (P<0.05) greater than that of OMC-encapsulated for all formulations investigated. OMC-free skin accumulation ranged from 127.8±22.8 μg/cm2 (O/W emulsion) to 172.1±12.9 μg/cm2 (W/O emulsion). OMC-encapsulated skin accumulation ranged from 50.3±13.1 μg/cm2 to 43.0±6.5 μg/cm2 at NC–O/W and NC–W/O, respectively. No significant differences were found in the transdermal permeation of cinnamate for any of the formulations tested. The results of this study demonstrate that the inclusion of OMC-encapsulated in sunscreen formulations decreases the skin accumulation of the cinnamate since the in vitro release mechanism of OMC-nanocapsules is governed by hydrophobicity and crystallinity of the polymer and by the high lipophilicity of the drug. The crystallinity of the polymer have the ability of reflecting and scattering UV radiation on their own thus leading to photoprotection without the need for molecular sunscreens.
Keywords: Sunscreen; Octyl methoxycinnamate (OMC); Nanocapsules (NC); Percutaneous penetration; Stripping technique;
Micellar solutions of triblock copolymer surfactants with pilocarpine by I Pepić; N Jalšenjak; I Jalšenjak (57-64).
Solutions of surface active triblock copolymer Pluronic F127 in the vicinity of the critical micellar concentration (cmc) were prepared with or without pilocarpine (either as the hydrochloride salt or the free base) in water and phosphate buffer. The characteristics parameters of the surface activity (cmc, Γ and a) were determined for F127 solutions. Additionally, it was found that the pilocarpine solutions without F127 in water exhibits a certain surface activity. The solutions containing F127 (2 wt.%) well above the cmc and pilocarpine (2 wt.% for the salt, or equimolar 1.7 wt.% for the base) were further tested in vivo (miotic response) on rabbit eye. Though the entrapment efficiency of the drug in the micelles was rather low (maximal 1.9%) the pharmacokinetic parameters (duration of miotic response and the area under miotic curve) were improved when compared to the standard pilocarpine solutions. The best results were obtained for the micellar pilocarpine base solution which exhibits significant prolongation of miotic activity and an increase of AUC for 64%.
Keywords: Pluronic F127; Pilocarpine; Surface tension; Critical micellar concentration; Miosis;
Therapeutic efficacy of sustained drug release from chitosan gel on local inflammation by K. Kofuji; H. Akamine; C.J. Qian; K. Watanabe; Y. Togan; M. Nishimura; I. Sugiyama; Y. Murata; S. Kawashima (65-78).
The model anti-inflammatory drug prednisolone (PS) was retained in chitosan (CS) gel beads, which were prepared in a 10% aqueous amino acid solution (pH 9.0). Sustained release of PS from the CS gel beads was observed. Carrageenan solution was injected into air pouches (AP), which were prepared subcutaneously on the dorsal surface of mice, in order to induce local inflammation. CS gel beads retaining PS were then implanted into the AP to investigate the therapeutic efficacy of sustained PS release against local inflammation. In vivo PS release from CS gel beads was governed by both diffusion of the drug and degradation of the gel matrix. Sustained drug release by CS gel beads allowed the supply of the minimum effective dose and facilitated prolonged periods of local drug presence. Inflammation indexes were significantly reduced after implantation of CS gel beads when compared with injection of PS suspension. Thus, extension of the duration of drug activity by CS gel beads resulted in improved therapeutic efficacy. These observations indicate that CS gel beads are a promising biocompatible and biodegradable vehicle for treatment of local inflammation.
Keywords: Chitosan; Sustained release; Inflammation; Biodegradation; Air pouch;
Development of parenteral formulation for a novel angiogenesis inhibitor, CKD-732 through complexation with hydroxypropyl-β-cyclodextrin by Jae-Hyun Kim; Su-Kyung Lee; Min-Hyo Ki; Won-Kyu Choi; Soon-Kil Ahn; Hee-Jong Shin; Chung Il Hong (79-89).
The effect of hydroxypropyl-β-cyclodextrin (HP-β-CyD) on the aqueous solubility and chemical stability of O-(4-Dimethylaminoethoxycinnamoyl)fumagillol (CKD-732), a new angiogenesis inhibitor, was investigated with an aim of preparing a stable and effective parenteral formulation. The CKD-732/HP-β-CyD inclusion complex was obtained in solid state by freeze-drying and characterized in solution by proton nuclear magnetic resonance ( 1 H NMR). Then, the pharmacokinetic profile in rats and the in vivo tumor growth inhibitory activity in mice following the parenteral administration of aqueous CKD-732/HP-β-CyD complex were compared to those of CKD-732·hemioxalate solution having an equivalent concentration. The aqueous solubility of CKD-732 was markedly increased by the combination of pH adjustment and HP-β-CyD complexation through a soluble 1:1 inclusion complex formation, which was supported by NMR spectroscopy. The hydrolysis of CKD-732 following pseudo first-order kinetics was decelerated moderately but significantly in acidic and basic solutions in the presence of HP-β-CyD. The stability of lyophilized CKD-732/HP-β-CyD complex was also drastically improved after storage in various conditions. The intravenous pharmacokinetic profile and the subcutaneous in vivo tumor growth inhibitory activity of aqueous CKD-732/HP-β-CyD complex were not significantly different from those of CKD-732·hemioxalate solution with the favorable reduction of irritation. These results demonstrate that the CKD-732/HP-β-CyD complex is an attractive formulation for use in the parenteral delivery of CKD-732.
Keywords: O-(4-Dimethylaminoethoxycinnamoyl)fumagillol (CKD-732); Angiogenesis inhibitor; Hydroxypropyl-β-cyclodextrin (HP-β-CyD); Solubilization; Stabilization;
Improvement of the ocular bioavailability of timolol by sorbic acid by Masayo Higashiyama; Katsuhiro Inada; Akira Ohtori; Kakuji Tojo (91-98).
The ocular bioavailability of timolol increased in sorbic acid solution due to ion pair formation. Its octanol/water partition coefficient also increased, suggesting the formation of a more lipophilic complex. The concentration of timolol in rabbit aqueous humor was determined after instillation of timolol ophthalmic solution containing sorbic acid. When the molar ratio of sorbic acid to timolol was two or higher, the concentration of timolol in the aqueous humor was higher than with timolol alone. In the presence of sorbic acid the maximal aqueous humor concentration and the area under the curve were more than two-fold higher than those of Timoptol®, a timolol maleate ophthalmic solution, and similar in value to TIMOPTIC-XE®, a gel-forming ophthalmic solution. To investigate the transcorneal absorption mechanism, in vitro permeation profiles across the intact and de-epithelialyzed cornea were analyzed on the basis of the bilayer diffusion model. The partition coefficient in the epithelium was about twice as high in the presence of sorbic acid than with timolol alone, although the diffusion coefficient in the epithelium did not change. We conclude that the improved ocular bioavailability in the presence of sorbic acid is due to increased partitioning of timolol in the corneal epithelium.
Keywords: Ocular bioavailability; Timolol maleate; Ophthalmic solution; Ion pair; Bilayer diffusion model;
Stomach-specific anti-H. pylori therapy by Radi Hejazi; Mansoor Amiji (99-108).
The main objective of the present study was to examine the effect of chemical crosslinking of chitosan microspheres on the gastric residence and local tetracycline concentrations following oral administration in fasted gerbils. Radioiodinated [ 125 I ] glyoxal-crosslinked chitosan microsphere suspension in deionized distilled water was administered for the gastric residence studies. At different time points, the animals were sacrificed and the radioactivity in tissues and fluids was measured. Stomach tetracycline concentrations were determined using tritiated-[ 3 H ]-tetracycline-loaded crosslinked chitosan microspheres. The radioactivity, measured with a liquid scintillation analyzer, was used to determine the microgram of drug per gram of tissues or fluids. After 2 h in the fasted stomach, approximately 10% of the non-crosslinked chitosan microspheres remained. On the other hand, 17% of the crosslinked chitosan microspheres remained in the fasted stomach after the same time period. The microspheres were predominantly found in the colon after 6 h of administration. There was no detectable radioactivity in the plasma, urine, small intestine, liver, and kidneys. Tetracycline concentration profile in the stomach from the crosslinked microsphere formulation was higher than that of the aqueous solution and the non-crosslinked microsphere formulation. While the area-under-the-curve ( AUC 0.5→10 h ) for tetracycline solution and non-crosslinked chitosan microspheres was 447.3 and 358.2 μg h/g of tissue, respectively, the AUC 0.5→10 h for the crosslinked chitosan microspheres was 868.9 μg h/g of tissue. The drug was predominantly found in the colon and urine after 6 h of administration. Results of this study show that chitosan microspheres prepared by chemical crosslinking provide a longer residence time in the fasted gerbil stomach than either tetracycline solution or microspheres prepared by ionic precipitation.
Keywords: Stomach-specific delivery; Chitosan microspheres; Chemical crosslinking; Glyoxal; Tetracycline; Helicobacter pylori; Gastric residence time;
Prolongation of epidural bupivacaine effects with hyaluronic acid in rabbits by Gilles Dollo; Jean-Marc Malinovsky; Alain Péron; François Chevanne; Michel Pinaud; Roger Le Verge; Pascal Le Corre (109-119).
To assess the prolongation of epidural bupivacaine by hyaluronic acid viscous formulations we designed a cross-over study in rabbits. Different doses of bupivacaine (3 or 6 mg) either as a solution (bupivacaine hydrochloride), or as viscous formulations with hyaluronic acid (bupivacaine base and bupivacaine hydrochloride) were administered in a rabbit model of epidural anesthesia. In the first part of the study, in vitro release characteristics were determined. Then pharmacodynamic effects and pharmacokinetic profiles of each bupivacaine formulation were studied. The rank order release rate of bupivacaine in vitro was always hydrochloride solution⪢viscous physical mixture of bupivacaine with hyaluronic acid>viscous ionic complex of bupivacaine base with hyaluronic acid. Onset time of epidural anesthesia was similar whatever the formulation of bupivacaine used. We did not find any blockade prolongation when 3 mg bupivacaine was administered, but significant blockade prolongations were observed with viscous formulations incorporating 6 mg bupivacaine. The observed reduction in the absorption rate of bupivacaine into the systemic circulation for both viscous hyaluronic formulations after 6 mg of bupivacaine may explain the prolongation of spinal effects. Drug release and duration of action were found to be viscosity controlled as linear relationships were found between pharmacodynamic effects and viscosity. Our results were in accordance with those reported with bupivacaine–cyclodextrin complex, another formulation with a molecular dispersion of the drug, resulting in a moderate prolongation of action.
Keywords: Bupivacaine; Epidural anesthesia; Hyaluronic acid; Rabbits;
The use of inverse gas chromatography to assess the acid–base contributions to surface energies of cefditoren pivoxil and methacrylate copolymers and possible links to instability by Masato Ohta; Graham Buckton (121-128).
It is known that acids and bases when mixed together have the potential to react, however, there is complexity when materials are in the solid state, as the surface of the solids may not have all functional groups of the molecule expressed in equal proportions. Conceptually a drug that is acidic when in solution could have a crystal surface that is largely basic (if the acid groups are aligned away from the surface). The interaction of cefditoren pivoxil (a basic drug when dissolved) and various Eudragit polymers was studied. The drug was chemically unstable with Eudragit EPO (basic) and stable with Eudragit L100 or S100 (both acidic). Thus, the hypothesis of this work was that the surface of these materials had a different nature to the dissolved molecules, such that solid state reactions do not proceed in line with the expectation from the solution state. Inverse phase gas chromatography (IGC) was used to investigate the cefditoren pivoxil and the Eudragits. The basic to acidic parameter ratios (K D/K A) on the powder surface of the samples by IGC revealed that surface nature was in keeping with the tendency to react, such that the incompatibility could be due to the acid–base interaction between any carbonyl groups having an amphoteric nature on the surface of cefditoren pivoxil crystal and dimethylaminoethyl groups having a basic nature on the powder surface of Eudragit EPO. This study indicated that IGC would be suitable to elucidate the cause of incompatibility between two different solids.
Keywords: Cefditoren pivoxil; Eudragit; Inverse gas chromatography; Surface energy; Stability;
Preparation and in vitro synergistic anticancer effect of Vitamin K3 and 1,8-diazabicyclo[5,4,0]undec-7-ene in poly(ethylene glycol)-diacyllipid micelles by Junping Wang; Dmitriy A Mongayt; Anatoly N Lukyanov; Tatiana S Levchenko; Vladimir P Torchilin (129-135).
Polymeric micelles consisting of poly(ethylene glycol)-distearoyl phosphoethanolamine conjugates (PEG-DSPE) loaded with Vitamin K3 (VK3) to 0.2 mg of drug/mg of carrier and with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) to 0.06 mg of drug/mg of carrier were prepared. These micelles were stable for as long as 6 months during storage at 4 °C and did not change their size or release the incorporated drugs. Co-encapsulation of VK3 and DBU into PEG-DSPE micelles resulted in synergistic anticancer effects against both murine and human cancer cells in vitro. The synergism may be explained by the fact that the presence of DBU promotes the escape of drug-loaded micelles from the endosomes of cancer cells directly into the cytoplasm as demonstrated by fluorescent microscopy.
Keywords: Polymeric micelles; PEG-PE; Anticancer drugs; Vitamin K3; 1,8-Diazabicyclo[5,4,0]undec-7-ene; Synergistic anticancer effect;
Power consumption measurement and temperature recording during granulation by Gabriele Betz; Pascale Junker Bürgin; Hans Leuenberger (137-149).
This study was performed to elucidate the influences of process and formulation design using power consumption and temperature measurements during granulation. Power consumption was recorded “in process” using a previously introduced computer program for optimal end-point detection at an early stage. The temperature increase (ΔT) during granulation was recorded using a temperature sensor. The temperature increase in the wet powder bed expresses the friction forces at interparticle contacts occurring during granulation. The maxima of temperature profile occurred at 130% saturation, whereas the maxima of power consumption were determined at 100% saturation. The ratio of temperature and power consumption (TPR factor) is introduced as a signature of formulation design. TPR factor was found to be dependent on particle size, particle surface, water absorption capacity and solubility of the excipient and model drug, respectively. However, TPR factor was found to be independent of process design, such as the filling level of the mixer.Understanding and controlling the granulation process is a key factor in robust dosage form design. The “in process” control fits ideally the prerequisites of a drug quality system for the 21st century and FDA’s Process Analytical Technology (PAT) initiative. The results of previous and present works of our research group will be used in a following step to develop an artificial neural network for granulation “in process” control.
Keywords: Granulation; Power consumption; Temperature control; In process control; Formulation design;
Effect of drug solubility and different excipients on floating behaviour and release from glyceryl monooleate matrices by Kiran Kumar M; Manish H. Shah; Anant Ketkar; K.R. Mahadik; Anant Paradkar (151-160).
Glycerol monooleate (GMO) matrix was found to be a gastro-retentive carrier system suitable for both polar and as well as non-polar drugs. Chlorpheniramine maleate (CPM) and diazepam (DZP) were used as model drugs. Effect of PEG 4000, PEG 10000, and stearic acid on floatability and release profile was studied.Water uptake increased with increase in the loading of polar drug (CPM) and decreased with non-polar drug (DZP). Similar effect was found to occur in case of drug release. PEGs increased the release up to certain concentration and decreased thereafter. Drug release decreased linearly with concentration of stearic acid. The type and extent of mesophases formed were significantly affected by the nature of drug, excipients and their concentration. Thus the selection of suitable excipients depending on polarity of drug, could help to modulate the floatability and release profile from GMO matrices.
Keywords: Glyceryl monooleate; Diazepam; Chlorpheniramine maleate; Liquid crystalline phases; Floating matrices;
Transport characteristics of 9-nitrocamptothecin in the human intestinal cell line Caco-2 and everted gut sacs by Xianyi Sha; Xiaoling Fang (161-171).
The intestinal absorptive characteristics and the efflux mechanisms of 9-nitrocamptothecin (9-NC), a novel water-insoluble camptothecin (CPT) derivative, were investigated. The Caco-2 cells and the everted gut sacs were used as models of the intestinal mucosa to assess transepithelial transport of 9-NC. The determination of 9-NC was performed by HPLC. In the Caco-2 cells, the absorptive transport of 9-NC was pH dependent and the transport was enhanced at weakly acidic pH on the apical side. No concentration dependence and saturation were observed for the absorptive transport of 9-NC at concentrations up to 250 μM, while secretory transport were concentration dependent and saturable process (K m was 49.8±1.2 μM, V max was 38.28±0.8 ng/cm2/min). In the presence of verapamil (100 μM) and CsA (10 μM), potent inhibitors of P-glyprotein (P-gp)/MRP2 (cMOAT), the P app BL-AP/P app AP-BL ratio was decreased from 3.4 to 1.4 and 1.3, respectively, and permeation of apical to basolateral was enhanced approximately two-fold. In the everted gut sacs, the absorption of 9-NC was passive diffusion and had no significant difference in different gut regions. Adding verapamil in the everted gut sacs over a concentration ranging from 10 to 100 μM, the absorption of 9-NC was significantly enhanced, especially more markedly in lower small intestine (P<0.05). Overall, the current study suggests that pH and efflux transporters are capable of mediating the absorption and efflux of 9-NC, and they may play significant roles in limiting the oral absorption of 9-NC.
Keywords: 9-Nitrocamptothecin; Caco-2 cells; P-glycoprotein; Intestinal transport; Everted gut sacs;
The influence of buffer composition on tissue integrity during permeability experiments “in vitro” by Simon Žakelj; Igor Legen; Marjan Veber; Albin Kristl (173-180).
A well-balanced incubation saline is necessary for permeability experiments with the rat jejunal tissue in the diffusion chambers. At the same time the investigated substance must be chemically stable and sufficiently soluble in this incubation saline. To investigate whether the absence of some ions in incubation salines influences the tissue viability and integrity or the diffusional characteristics of the epithelial membrane the electrical parameters were monitored and the permeability of fluorescein and acyclovir was evaluated during the experiments in side-by-side diffusion chambers. Our results show that the tissue integrity and viability are seriously impaired when Ca2+ and Mg2+-free conditions are applied on both sides of the diffusion chambers, but not when only mucosal or only serosal side is Ca2+ and Mg2+-free. Bicarbonate-free incubation salines can also alter the measured apparent permeability coefficients even though the tissue viability and integrity do not change. This change in the apparent permeability is most likely due to a change in the pH of the mucosal surface and can be prevented if the buffer capacity of the incubation saline is increased.
Keywords: Rat jejunum; Diffusion chambers; Modified incubation saline; Permeability; Ca2+ and Mg2+; Bicarbonate;
Study of the phase behavior of polyethylene glycol 6000–itraconazole solid dispersions using DSC by Xin Wang; Armand Michoel; Guy Van den Mooter (181-187).
The aim of the present study was to investigate the phase behavior of solid dispersions made up of PEG 6000 and itraconazole using DSC. Solid dispersions were prepared by solvent evaporation. DSC analysis of pure PEG 6000 showed three endothermic events, representing the melting transitions of the three different crystal modifications. It was shown that itraconazole decreased the formation of the polymer modifications with melting transitions at 56 and 59 °C but promoted the formation of the modification with a melting transition at 63 °C. All dispersions investigated showed the presence of crystalline itraconazole indicating that the drug is not molecularly dispersed in the polymer matrix. However, the presence of an endothermic peak in DSC curves of all solid dispersions at approximately 85–90 °C showed that at least a second phase of pure itraconazole is present also: glassy itraconazole. The protective effect of the polymer is clear at low concentration of drug since no recrystallisation exotherm can be detected. However, at drug concentrations at or above 80%, a recrystallization exotherm at approximately 117 °C can be detected. At least three different phases can be distinguished at room temperature: a polymer phase, crystalline itraconazole and glassy itraconazole. The findings of the present study thus demonstrate the coexistence of multiple drug phases in a solid dispersion.
Keywords: Polyethylene glycol 6000; Itraconazole; Differential scanning calorimetry (DSC); Phase separation;
Successful in silico predicting of intestinal lymphatic transfer by René Holm; Jan Hoest (189-193).
The possibility of developing a quantitative relationship between molecular structure and lymphatic transfer of lipophilic compounds co-administered with a long-chain triglyceride vehicle was examined. Molecular descriptors were calculated using the computer program VolSurf, and lymphatic transfer data were derived from the literature. A significant structure–property relationship was established using partial least squares, projection to latent structures statistics (PLS). R 2 X was 0.77, R 2 Y was 0.83 and the prediction power of Q 2 was 0.73 in the two-component PLS model. A number of descriptors contributed to the prediction leading to a complex model, but the prediction power was improved with the PLS model when compared to the frequently used method by relating log P values (LogKow) with lymphatic transfer.
Keywords: Lymph; Lipid; Triglyceride; In silico prediction; VolSurf; PLS;