International Journal of Pharmaceutics (v.202, #1-2)
Biodistribution of fluoresceinated dextran using novel nanoparticles evading reticuloendothelial system by Upasna Gaur; Sanjeeb Kumar Sahoo; Tapas K De; Prahlad C Ghosh; Amarnath Maitra; P.K Ghosh (1-10).
The rapid clearance of circulating nanoparticles from the blood stream coupled with their high uptake by liver and spleen has thus far been overcome by reducing the particle size, and by making the particle surface hydrophilic with poloxamers and poloxamines. We have prepared hydrogel nanoparticles of polyvinylpyrrolidone of a size less than 100 nm diameter with precise size distribution. Since the inner cores of these particles are also hydrophilic, these particles are capable of encapsulating water-soluble compounds. Biodistribution of these particles shows practically negligible (<1%) uptake by the macrophages in liver and spleen, and ∼5–10% of these particles remain in circulation even 8 h after i.v. injection. Increasing the surface hydrophobicity as well as particle size can increase the RES uptake of these particles. Because of longer residence in blood, the hydrogel nanoparticles have potential therapeutic applications particularly in cancer: the water-soluble cytotoxic agents encapsulated in these particles can be targeted to tumors while minimizing the likelihood of toxicity to reticuloendothelial system (RES).
Keywords: Hydrogel nanoparticles; Long circulating nanoparticles; Polyvinylpyrrolidone; Drug targeting; RES evasion;
A novel approach for delivery of enzyme drugs: preliminary demonstration of feasibility and utility in vitro by Jun F Liang; Yong T Li; Victor C Yang (11-20).
A novel heparin/protamine-based approach for delivery of enzyme drugs without associated toxic effects has been proposed. This approach would allow an enzyme drug to be administered in an inactive (i.e. pro-drug) form and then released at the target site in an active form using protamine as the triggering agent. The pro-drug and the triggered release features of this approach would permit the enzyme drug to act specifically and only on its target substrates while sparing normal substrates, thereby alleviating unwanted toxic effects. The in vitro feasibility of the approach has been successfully demonstrated using trypsin as the model protease drug. In addition, the utility of the approach has also been demonstrated by applying the system in delivering streptokinase, one of the most widely used clinical drugs in thrombolytic therapy. This approach may open up the possibility of developing a wide range of new catalytic drugs that are initially thought to be impossible for therapeutic use due to their potent toxic effects.
Keywords: Heparin; Protamine; Pro-drug feature; Triggered release feature; Enzyme drugs; Streptokinase;
Fronts movement as a useful tool for hydrophilic matrix release mechanism elucidation by C Ferrero; A Muñoz-Ruiz; M.R Jiménez-Castellanos (21-28).
The purpose of this study was to modify the fronts movement method proposed by Colombo et al. in order to apply it to uncoloured drugs and hydrophilic non-swellable matrices. Matrix tablets were prepared using theophylline as a model drug and sodium carboxymethylcellulose (NaCMC) or a new graft copolymer, hydroxypropylcellulose methylmethacrylate dried by lyophilization (HCMMAL), as polymer carriers. Drug release experiments were performed from the whole tablets. Radial drug release and fronts movement were also evaluated using special devices consisting of two Plexiglass® discs joined by means of four stainless steel screws. Release kinetics were determined by means of Higuchi, Korsmeyer and Peppas equations and were related to the fronts movement data. The analysis of drug release and fronts movement kinetics revealed a different release mechanism for both matrices. Drug release from NaCMC matrices was mostly controlled by relaxation, whereas drug diffusion through the porous network regulated drug release from HCMMAL matrices. A reduction in the surface exposed to the dissolution medium led to a decrease in the drug release rate, but the release mechanism was not essentially modified. Fronts movement was shown as a useful tool for matrix release mechanism elucidation. A new denomination for the different fronts observed in HCMMAL matrices was proposed.
Keywords: Hydroxypropylcellulose methylmethacrylate; Sodium carboxymethylcellulose; Moving front kinetics; Image analysis; Drug release mechanism; Matrix tablet;
Chitosan microspheres in PLG films as devices for cytarabine release by M.D Blanco; C Gómez; R Olmo; E Muñiz; J.M Teijón (29-39).
Cytarabine was included in chitosan microspheres and several of these microspheres were embedded in a poly(lactide-co-glycolide) (PLG) film to constitute a comatrix system, to develop a prolonged release form. Chitosan microspheres, in the range of 92±65 μm, having good spherical geometry and a smooth surface incorporating cytarabine, were prepared. The cytarabine amount included in chitosan microspheres was 43.7 μg of ara-C per milligram microsphere. The incorporation efficiency of the cytarabine in microspheres was 70.6%. Total cytarabine release from microspheres in vitro was detected at 48 h. Inclusion of cytarabine-loaded microspheres in poly(lactide-co-glycolide) film initiated a slower release of the drug and, in this way, the maximum of cytarabine released (80%) took place in vitro at 94.5 h. Comatrices, with 8.7 mg of cytarabine, signifying a dose of 34.5 μg/kg, were subcutaneously implanted in the back of rats. Maximum plasma cytarabine concentration was 18.5±1.5 μg/ml, 48 h after the device implantation and the drug was detected in plasma for 13 days. The histological studies show a slow degradative process. After 6 months of implantation, most of the microspheres of the matrix seemed to be intact, the comatrix appeared surrounded by conjunctive tissue and small blood vessels and nerve packets were detected in the periphery of the implant.
Keywords: Cytarabine; Chitosan microspheres; Poly(lactide-co-glycolide) film; Pharmacokinetic; Histological studies;
Relationship between potency and boiling point of general anesthetics: a thermodynamic consideration by Siavoush Dastmalchi; Mohammad Barzegar-Jalali (41-45).
The most important group of nonspecific drugs is that of the general anesthetics. These nonspecific compounds vary greatly in structure, from noble gases such as Ar or Xe to complex steroids. Since the development of clinical anesthesia over a century ago, there has been a vast amount of research and speculation concerning the mechanism of action of general anesthetics. Despite these efforts, the exact mechanism remains unknown. Many theories of narcosis do not explain how unconsciousness is produced at a molecular level, but instead relate some physicochemical property of anesthetic agents to their anesthetic potencies. In this paper, we address some of those physicochemical properties, with more emphasis on correlating the anesthetic potency of volatile anesthetics to their boiling points based on thermodynamic principles.
Keywords: Volatile anesthetics; Boiling point; Anesthetic potencies; Thermodynamics; Ferguson principle;
Kinetic study of the reaction of sulfamethoxazole and glucose under acidic conditions by H. Lucida; J.E. Parkin; V.B. Sunderland (47-62).
The kinetics of the reaction of sulfamethoxazole (SMX) in 5% w/v glucose to form the corresponding α- and β-glucosylamines over the pH range of 0.80–6.88 at 37°C has been investigated. The identity of the glucosylamines was determined by 1H-nuclear magnetic resonance spectroscopy of an authentic sample of the α-glucosylamine (USP) and the reaction products, and by interconversion of this compound to the corresponding β-anomer. The reaction followed pseudo first-order reversible kinetics and involved specific acid and general acid–base catalysis. The pH-rate profile demonstrated that over the pH range of 0.80–2.90 and 5.50–6.88 the reactions were dependent on H+ concentration but pH independent between pH 3.00–5.45, which reflects the influence of ionization of SMX and the glucosylamines on the reversible reaction. Interpretation of the data with respect to kinetic models and rate equations for the formation and hydrolysis of the glucosylamines was investigated. Temperature dependence studies followed the Arrhenius equation with an Ea of 49.28 kJ mol−1 for the forward and 63.46 kJ mol−1 for the reverse reaction at pH 2.89 respectively.
Keywords: Dextrose; Glucose; Glucosylamines; Kinetics; Reversible reactions; Sulfamethoxazole;
Influence of Vitamin E TPGS on the properties of hydrophilic films produced by hot-melt extrusion by Michael A Repka; James W McGinity (63-70).
Films containing hydroxypropylcellulose (HPC) and polyethylene oxide (PEO) were prepared using a Randcastle extruder (Model 750) with and without Vitamin E TPGS (TPGS, d-α-tocopheryl polyethylene glycol 1000 succinate) as an additive. Conventional plasticizers including polyethylene glycol 400 (PEG 400), triethyl citrate (TEC), and acetyltributyl citrate (ATBC) were also incorporated into films containing a 50:50 blend of HPC and PEO. The physical–mechanical properties including tensile strength (TS) and percent elongation (%E) were determined on an Instron according to the ASTM standards. Glass transition temperatures (T g) of the extruded films were determined utilizing a DSC 2920 Modulated differential scanning calorimeter and thermal analyst 2000 software. Gel permeation chromatography was used to study the stability of the polymer films under the processing conditions. The addition of 1, 3, and 5% Vitamin E TPGS, respectively, decreased the glass transition temperature of the extruded films containing either a 50:50 or 80:20 ratio of HPC to PEO in an almost linear fashion. In addition, the presence of 3% Vitamin E TPGS lowered the T g over 11°C when compared with the HPC/PEO 50:50 blend film without TPGS, thus functioning as a plasticizer. The tensile strength decreased with increasing concentrations of TPGS, and the %E increased over 3-fold when compared with the HPC/PEO film that contained no additives. The film containing 3% Vitamin E TPGS had a similar tensile strength to that of the films containing 3% PEG 400, and a 3-fold increase in percent elongation when compared with the films containing 3% TEC and 3% ATBC. In addition, the Vitamin E TPGS facilitated the processing of the HPC/PEO films by decreasing the barrel pressure, drive amps, and torque of the extruder equipment.
Keywords: Vitamin E TPGS; Hot melt; Extruded films; Hydroxypropylcellulose; Physical–mechanical properties; Glass transition temperature; Polyethylene oxide;
Calorimetry a method to be used to characterise pyrolytically decarboxylated bicarbonate and assess its stability at elevated humidities by Lennart Ljunggren; Natalia Volkova; Henri Hansson (71-77).
Microcalorimetry was used to characterise bicarbonate after treatment at high temperatures. By measuring the heat flow from a sample of bicarbonate at 100% relative humidity, the net exothermic contribution could be used to estimate the fraction of pyrolytically formed Na2CO3. The enthalpy value corresponding to the heat of solution of Na2CO3 was also applicable to a physical mixture of NaHCO3/Na2CO3. However, from the characteristic peaks of the heat flow versus time curve, pyrolytically formed Na2CO3 could be distinguished from that present in the physical mixture. The different bicarbonate batches of varying degree of pyrolytic decarboxylation were also observed at an elevated relative humidity of 54%. From these measurements it could be inferred that a decarboxylation of up to 4.5% could be allowed without any significant effect on the stability of bicarbonate at 54%.
Keywords: Calorimetry; Sodium bicarbonate; Sodium carbonate; Relative humidity; Enthalpy; Pyrolytic decarboxylation;
Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs by Francesco P Bonina; Loredana Arenare; Rosa Ippolito; Gianpiero Boatto; Giuseppe Battaglia; Valeria Bruno; Paolo de Caprariis (79-88).
7-Chlorokynurenic acid 1 is a potent glycine-N-methyl-d-aspartate (NMDA) receptor antagonist, but it shows weak activity after systemic administration. In order to overcome the Blood–brain barrier (BBB), we synthetized three new esters 2–4 of 1 obtained by chemical conjugation with essential nutrients such as glucose and galactose, that are actively transported across the BBB. These compounds were assayed to evaluate their in vitro chemical and enzymatic hydrolysis. In addition the prodrugs 2–4 were tested for their ability to protect mice against NMDA-induced seizures after systemic administration. All the prodrugs 2–4 appeared moderately stable in pH 7.4 buffered solution and were susceptible to in vitro enzymatic hydrolysis. Intraperitoneal administration of either esters 2 or 4 was highly protective against seizures induced by NMDA in mice, with the latter prodrug showing the highest anticonvulsive activity. In addition, ester 4 undergoes a time-dependent extracellular hydrolysis into 1 when applied to mixed cultures of mouse cortical cells, a model that reproduces in vitro the cellular milieu encountered by the prodrugs once they penetrate the brain parenchyma.
Keywords: Prodrug; 7-Chlorokynurenic acid; Blood–brain barrier; NMDA-receptor; Anticonvulsant;
Pharmacokinetics and absolute bioavailability of oral cefuroxime axetil in the rat by P. Ruiz-Carretero; A. Nacher; M. Merino-Sanjuan; V.G. Casabo (89-96).
The objectives of this study were to determine the oral bioavailability of cefuroxime (C) and to evaluate the pharmacokinetic model that best describes the plasma concentration behaviour following single intravenous (IV), intraperitoneal (IP) and oral single doses. The same dose of C was administered by IV, IP and oral routes to three separate groups of rats (2.02 mg of cefuroxime axetil (CA) by the oral route or 1.78 mg of cefuroxime sodium (CNa) by IV and IP route). A two-compartment open model without lag time can predict the C disposition kinetics. The influence of the administration route on the pharmacokinetic parameters and AUC values was investigated by means of a one-way analysis of variance test. The results indicated that the first-pass effect in the intestine and liver reduce oral biovailability when the drug is admistered orally. Cefuroxime bioavailability after oral and IP administration estimated from the plasma levels was nearly 24 and 75%, respectively.
Keywords: Cefuroxime axetil; Pharmacokinetic model; Absolute bioavailability; Rat;
Pharmacokinetics of metoprolol enantiomers following single and multiple administration of racemate in rat by S.Abolfazl Mostafavi; Robert T. Foster (97-102).
The chiral β-adrenergic blocking agent metoprolol (MET), which is marketed as a racemate, is a highly extracted drug with rapid absorption. The enantiomeric disposition of MET is reported following racemic administration as a single and as multiple oral dosing four times per day for four days in male Sprague–Dawley rats (n=6 in each group). Plasma was collected and enantiomeric concentrations of MET were determined using a stereospecific HPLC assay. The R/S ratio for AUC is not statistically different from unity either after single or after multiple administration of racemate. The oral clearance after single dose was 1.99±0.87 and 2.26±0.85 ml min−1 kg−1 for R- and S-MET, respectively. These values were decreased to 0.59±0.21 and 0.64±0.26 ml min−1 kg−1 after multiple administration of racemate. The corresponding values for the elimination half-lives were approximately 35 and 33 min after single and multiple dose administration for both enantiomers, respectively. These results may suggest a saturable first pass metabolism of MET as its enantiomers are accumulated in plasma following multiple dosing in the rat model.
Keywords: Metoprolol; Pharmacokinetics; Enantiomers; Single dose; Multiple dose;
Polyoxyethylene-poly(methacrylic acid-co-methyl methacrylate) compounds for site-specific peroral delivery by V Carelli; G Di Colo; E Nannipieri; B Poli; M.F Serafini (103-112).
pH-sensitive interpolymer interactions between high molecular weight polyoxyethylene (POE) and poly(methacrylic acid-co-methyl methacrylate) (Eudragit (EUD) L100 or S100) are evidenced and exploited to prepare, from either POE–EUD coevaporates or POE+EUD physical mixtures, both in the 1:1 wt. ratio, compressed matrix tablets, potentially able to deliver the model drug, prednisolone, to sites in the GI tract characterized by specific pHs, such as the jejunum or the ileum. With these devices, drug release is inhibited at pHs lower than the threshold of EUD ionization, whereas at pHs exceeding such a threshold, the matrix undergoes a gradual erosion, which controls the release. A post-compression exposure of tablets to the vapors of appropriate solvents realizes the necessary compaction of matrices, in fact, a high compression force (3 ton) is insufficient, per se, to prevent matrix disintegration in the dissolution medium, whereas such a disintegration is prevented by the treatment with solvent vapors, even with a low compression force (0.3 ton). With the POE+EUD physical mixtures, the exposure to solvent vapors promotes the formation of a layer of POE–EUD complex at the interfaces of the POE and EUD particles in matrix, which inhibits release at pHs lower than that designed for delivery. Both POE and EUD concur to determine the properties of the POE–EUD complex relevant to drug release, indeed, EUD ionization, which elicits matrix erosion and drug release, is favored by the hydrophilic POE. In fact, matrices based on plain EUD exhibit a comparatively low release rate, more suited to an extended delivery to the colon than to a specific delivery to the ileum. Details of the release mechanism are discussed.
Keywords: Polyoxyethylene; Eudragit; Interpolymer complex; Prednisolone; Oral delivery system; Site-specific delivery system; pH-sensitive release system;
Selective determination of pyridoxine in the presence of hydrosoluble vitamins using a continuous-flow solid phase sensing device with UV detection by M.J Ayora Cañada; M.I Pascual Reguera; A Molina Dı́az (113-120).
A very simple, inexpensive and highly selective flow injection UV spectrophotometric method for the determination of vitamin B6 is presented. The native absorbance of the analyte is continuously monitored at 290 nm when it is transiently retained on Sephadex SP C-25 cation exchanger gel beads placed in the detection area of a flow cell. The preconcentration on the active solid phase provides by itself a high increase in sensitivity compared with the same procedure carried out without a solid support. The analytical response is linear in the concentration ranges 1–10 and 2–20 μg ml−1 using 600 and 1250 μl of sample, respectively. The R.S.D. (%) are 0.65 (600 μl) and 0.84 (1250 μl) and the detection limits 0.08 and 0.02 μg ml−1, respectively. The procedure was successfully applied to the determination of vitamin B6 in pharmaceuticals containing (among other active principles) hydrosoluble vitamins in much higher concentrations than that tolerated by the method if performed in aqueous solution. Nevertheless they were tolerated using the proposed sensor due to the selective retention of the analyte.
Keywords: Pyridoxine; Flow injection UV spectrophotometry; UV sensing device;
Enhanced transdermal delivery of tetracaine by electroporation by Qiaohong Hu; Wenquan Liang; Jiali Bao; Qineng Ping (121-124).
The effect of electroporation on the transport of tetracaine through skin in vitro was studied using side-by-side compartment diffusion cells method. After achieving steady state by passive diffusion, fluxes of tetracaine achieved with passive diffusion, electroporative pulse and iontophoresis were compared. Electroporation (square-wave pulse, voltage 130 V, pulse time 0.4 s, pulse frequency 40 pulses min−1) or iontophoresis (0.2 · mA cm−2, lasting for 4 h) increased the transport of tetracaine through skin. The flux of tetracaine at 0.25 h after electroporation (pulse number 400) was 54.6±6.0 μg · cm−2 · h−1, that after iontophoresis was 17.4±5.8 μg · cm−2 · h−1 and that after passive diffusion was 8.2±0.5 μg · cm−2 · h−1. In addition, the fluxes of tetracaine increased with the increasing of pulse number. From these results, it is clear that electroporation is effective in enhancing transdermal delivery of tetracaine and its function is better than iontophoresis.
Keywords: Electroporation; Transdermal transport; Tetracaine; Iontophoresis;
Intranasal bioavailability of apomorphine from carboxymethylcellulose-based drug delivery systems by Michael Ikechukwu Ugwoke; Giana Kaufmann; Norbert Verbeke; Renaat Kinget (125-131).
Carboxymethyl cellulose (CMC) powder formulation of apomorphine was prepared by lyophilization and characterized with respect to the in vitro and intranasal in vivo release of apomorphine in rabbits. This was compared to apomorphine release from degradable starch microspheres (DSM) and lactose, as well as in vivo absorption after subcutaneous injection. In vitro apomorphine release from CMC was sustained, unlike that of DSM and lactose. Changing the drug loading of CMC from 15 to 30% (w/w) influenced drug release rate, which increased with increased drug loading. In vivo absorption of apomorphine from lactose, DSM and subcutaneous injection were rapid and not sustained. Slower absorption rates of apomorphine occurred from CMC. The fastest absorption rate was obtained with lactose and the slowest with CMC of 15% (w/w) drug loading. The T max from the CMC dosage forms were significantly prolonged compared to the immediate release forms. Plasma drug levels were sustained with CMC. The plasma concentration was maintained within 50% of the C max, longer (15% (w/w), 70 min; 30% (w/w), 40 min) compared to the rest (lactose, 20 min; DSM, 25 min, subcutaneous injection, 35 min). The sustained plasma level of apomorphine by CMC was achieved with relative bioavailabilities equivalent to subcutaneous injection.
Keywords: Apomorphine; Parkinson’s disease; Nasal drug delivery; Controlled release; Carboxymethylcellulose; Microspheres;
Comparative enhancer effects of Span®20 with Tween®20 and Azone® on the in vitro percutaneous penetration of compounds with different lipophilicities by A López; F Llinares; C Cortell; M Herráez (133-140).
Sorbitan monolaurate (Span®20) was used in this study to analyze the influence of the polar functional group on the effects that non-ionic surfactants have on skin permeability. Its ethoxylate derivative polysorbate 20 (Tween®20) and Azone®, both with the same C12 alkyl chain as Span®20, were used for comparative purposes. We evaluated the relative potency of the three molecules as enhancers in the permeability of a series of compounds with lipophilicities ranging from log Poct=−0.95 to log Poct=2.33. The influence of the enhancer concentration was also studied. For this purpose the epidermis of Wistar rat was pretreated with ethanolic solutions (1 and 5%, w/v) of each enhancer. Our results indicate that the nature of the enhancer head group greatly influences cutaneous barrier impairment. The enhancer concentration must also be taken into account, even though the influence of the concentration seems to depend on the lipophilicity of the penetrant assayed.
Keywords: Azone®; Span®20; Tween®20; Non-ionic surfactants; Enhancer concentration; Skin permeability;
Characterisation of instantaneous water absorption properties of pharmaceutical excipients by P Hedenus; M Strømme Mattsson; G.A Niklasson; O Camber; R Ek (141-149).
Powders absorb water by both capillary imbibition and swelling. The capillary process is almost instantaneous but swelling occurs over a period of time. An isothermal transient ionic current technique was used in this study to characterise the instantaneous absorption properties (rate and capacity) of a few selected pharmaceutical excipients. The results indicate that the instantaneous and long term water absorption properties of pharmaceutical powders can differ considerably. The rate of instantaneous water absorption appears to correlate with the total surface area while the absorption capacity correlates more with the porosity of the powder.
Keywords: Water absorption; Rate; Capacity; Pharmaceutical powders;
Specific gene transfer mediated by galactosylated poly-l-lysine into hepatoma cells by Junghee Han; Young Il Yeom (151-160).
Plasmid DNA/galactosylated poly-l-lysine(GalPLL) complex was used to transfer luciferase reporter gene in vitro into human hepatoma cells by a receptor-mediated endocytosis process. DNA was combined with galPLL via charge interaction (DNA:GalPLL:fusogenic peptide, 1:0.4:5, w/w/w) and the resulting complex was characterized by dynamic light scattering, gel retardation assay and zeta potential analyzer to determine the particle size, electrostatic charge interaction, and apparent surface charge. The complex was tested for the efficiency of gene transfer in cultured human hepatoblastoma cell line Hep G2 and fibroblast cells NIH/3T3 in vitro. The mean diameter of the complex (DNA:GalPLL=1:0.4, w/w) was 256±34.8 nm, and at this ratio, it was positively charged (zeta potential of this complex was 10.1 mV). Hep G2 cells, which express a galactose specific membrane lectin, were efficiently and selectively transfected with the RSV Luc/GalPLL complex in a sugar-dependent manner. NIH/3T3 cells, which do not express the galactose-specific membrane lectin, showed only a marginal level of gene expression. The transfection efficiency of GalPLL-conjugated DNA complex into Hep G2 cells was greatly enhanced in the presence of fusogenic peptide that can disrupt endosomes, where the GalPLL-DNA complex is entrapped with the fusogenic peptide. With the fusogenic peptide KALA, the luciferase activity in Hep G2 cells was ten-fold higher than that of cells transfected in the absence of the fusogenic peptide. Our gene transfer formulation may find potential application for the gene therapy of liver diseases.
Keywords: Receptor-mediated gene delivery; Galactosylated poly-l-lysine; Molecular conjugate; Hepatoma cells;
Increased partitioning of pilocarpine to the oily phase of submicron emulsion does not result in improved ocular bioavailability by Malgorzata Sznitowska; Katarzyna Zurowska-Pryczkowska; Ewa Dabrowska; Stanislaw Janicki (161-164).
Submicron emulsions containing pilocarpine as ion-pair with mono-dodecylphosphoric acid were prepared. Physical stability of these preparations was confirmed during 4 months of storage at 4°C. Approximately 50% of the drug was found in the aqueous phase of emulsion separated using an ultrafiltration technique, while the rest was present in the oily phase and interphase. The miotic effect observed in rabbits after application of the ion-pair in aqueous solution or in submicron emulsion was the same; indicating that the drug distribution into the oily phase of the colloidal vehicle does not improve ocular bioavailability.
Keywords: Pilocarpine ion-pair; Submicron emulsion; Miotic effect;
Oral bioavailability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes by F Veiga; C Fernandes; F Teixeira (165-171).
The purpose of the present study was to evaluate the enhancement of tolbutamide (TBM) oral bioavailability and hypoglycaemic activity through complexation with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD). TBM and its freeze-dried inclusion complexes were administered to rabbits (New zealand breed; n=6), in a dose of 20 mg/kg. TMB plasma levels were measured by HPLC and glucose levels were analysed according to Trinder (Trinder, P., 1969. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann. Clin. Biochem. 6, 24–28). The pure drug attained a maximum of plasma concentration (C max) of 18.58±3.27 μg/ml at 8.5 h (T max), whereas with inclusion complexes, C max increased about two times and appeared at ca. 4 h. AUC0–24 of complexes was about 1.6 times as much as that of the pure drug. Thus, the extent of oral absorption of TBM from inclusion complexes was significantly greater and faster when compared with drug alone. In addition, without cyclodextrins the maximum hypoglycaemic effect (CVGmax) of TBM (34.1%) was observed at 5.6 h (Tg max). CVGmax of TBM/β-CD and TBM/HP-β-CD inclusion complexes were 34.1% (at 6.5 h) and 37.7% (at 5.1 h), respectively. AAC0–24 of inclusion complexes was 1.4 times larger than that of pure drug. Hence, the oral administration of complexed TBM not only improved the drug absorption, but also the TBM hypoglycaemic activity.
Keywords: Cyclodextrins; Tolbutamide; Inclusion complexes; Bioavailability; Hypoglycaemic activity;
Effect of hydroxypropylmethylcellulose (HPMC) on the release profiles and bioavailability of a poorly water-soluble drug from tablets prepared using macrogol and HPMC by Tatsuya Ishikawa; Yoshiteru Watanabe; Kazuo Takayama; Hisashi Endo; Mitsuo Matsumoto (173-178).
The aim of the present study was to investigate the effect of hydroxypropylmethylcellulose (HPMC-2208), used as an excipient for controlled release of drug, on the release profiles and bioavailability of the poorly water-soluble nifedipine (NP) from a tablet prepared using macrogol 6000 (PEG) and HPMC. The crushing tolerance of the NP tablet prepared using PEG and HPMC (NP-PEG-HPMC tablet) was markedly increased with increasing compression force used during the preparation from 20 to 200 MPa. The values reached their maximal levels (approximately 13 kg for the NP-PEG-HPMC tablet and 8 kg for the PEG tablet) at the compression force of 100 MPa. Although NP is a poorly water-soluble drug, it was rapidly dissolved from the NP-PEG tablet (without HPMC) due to the improvement of its dissolution rate in the presence of PEG. NP dissolution was complete at the latest within 1 h. On the other hand, dissolution of NP from the NP-PEG-HPMC tablet was significantly delayed with an increase in the concentration of HPMC in the tablet. The dissolution of NP from the NP-PEG-HPMC tablet containing 50% HPMC-2208 was markedly delayed as the viscosity of HPMC also increased. Interestingly, the same peak plasma NP concentration (C max) and the area under the plasma NP concentration–time curve (AUC0–10) were observed for both the NP-PEG tablet and NP-PEG-HPMC tablets, however, the time to C max (t max) for the NP-PEG-HPMC tablet was significantly higher when the NP-PEG-HPMC tablet was orally administered to rabbits. We describe here a preparation method of a new sustained-release NP-PEG-HPMC tablet using a mixture of NP-PEG granules (prepared with PEG) and HPMC.
Keywords: Hydroxypropylmethylcellulose; Macrogol 6000; Sustained release tablet; Nifedipine;