International Journal of Pharmaceutics (v.239, #1-2)
Effects of dehydration temperature on water vapor adsorption and dissolution behavior of carbamazepine by Makoto Ono; Yuichi Tozuka; Toshio Oguchi; Shigeo Yamamura; Keiji Yamamoto (1-12).
Anhydrous carbamazepine was prepared by heating carbamazepine dihydrate at 60, 80, 100, 120, and 140 °C and used to investigate the effects of dehydration temperature on water vapor adsorption and dissolution behavior. The hydration rate of anhydrous carbamazepine at 75, 83, and 95% relative humidity and 25 °C decreased with increasing heating temperature. From the dissolution study by the rotating disk method, the calculated solubility of anhydrous carbamazepine was about 2.5 times higher than that of the dihydrate. The rate of phase transformation from the anhydrous form into the dihydrate during the dissolution process decreased with an increase in sample preparation temperature. These phenomena were further studied by thermal analysis, specific surface area measurement, density measurement, small-angle X-ray scattering, and wide-angle powder X-ray diffraction. As the heating temperature was raised, the specific surface area was reduced and the density was increased; furthermore, the average of the solid part calculated by the Debye method with small-angle X-ray scattering increased. The anhydrous carbamazepine prepared at lower heating temperatures was found to have a more porous structure and was seen by wide-angle powder X-ray diffraction to comprise both anhydrous forms I and II.
Keywords: Carbamazepine; Dehydration temperature; Hydration rate; Dissolution rate; Small-angle X-ray scattering;
Adsorption of an ionizable drug onto microspheres: experimental and modeling studies by Vincent Boudy; Nicolas Voute; Dominique Pradeau; Jean Claude Chaumeil (13-22).
The purpose of this work was to study the in vitro equilibria and the adsorption kinetics of an ionizable drug, indomethacin, onto commercially available cationic polymeric microspheres: DEAE Trisacryl LS and QA Trisacryl LS. Isotherms were fitted to theoretical equations allowing accurate predictions of drug loading at different salt concentrations. Isotherm measurements were quickly obtained by simple column breakthrough experiments. The nature of the ion exchange group of the microspheres was observed to be preponderant for adsorption, as the tertiary amine derivative exhibited 53% more capacity than its quaternary amine counterpart. The maximum equilibrium uptake capacity in a 5 mM Tris–HCl buffer at pH 7.4 is 303 mmol/ml of particle volume, for DEAE microspheres. Transport properties of indomethacin into the tertiary amine microspheres were obtained in agitated contactor. Microbeads loading was completed in a 1–6 min range and was found to be controlled by pore diffusion mechanism. Equilibrium uptake data was fitted to the Langmuir and the mass action law models. Adsorption kinetics were fitted to a pore diffusion model. Good correlation was obtained between the theoretical models and the experimental data. The methodology outlined in this work provided a simple approach of estimating adsorption behavior of drugs onto ion-exchange macroporous microspheres. Although significant indomethacin loading was obtained onto the DEAE microspheres, the rapid rate of diffusion is not compatible with sustained release properties sought for this type of microspheres.
Keywords: Microspheres; Cation exchange resins; Diffusion; Adsorption;
On computational control of flow in airblast atomisers for pulmonary drug delivery by R.V.N. Melnik; David R. Jenkins (23-35).
Among different approaches to successful pharmacotherapy the pulmonary drug delivery (PDD) mode plays an increasingly important role. In this paper PDD systems based on air-blast atomisation have been analysed mathematically. In order to allow the bioengineer to estimate the degree of effectiveness of a specific system prototype and to lay the basic principles for design, a conservation-law-based mathematical model is discussed. Key control parameters that allow improvement in the efficiency of the system have been identified and main characteristics of the system have been analysed numerically as functions of these parameters.
Keywords: Pulmonary drug delivery systems; Airblast atomisation; Mathematical models;
Role of poly [dl-lactide-co-glycolide] in development of a sustained oral delivery system for antitubercular drug(s) by Q. Ain; S. Sharma; S.K. Garg; G.K. Khuller (37-46).
An oral formulation based on poly (dl-lactide-co-glycolide) (PLG) microparticles was developed for delivery of antituberculous drugs. PLG entrapped antitubercular drugs when administered orally, were found to release the drugs in a sustained manner. This formulation was found to be stable in the acidic environment of gastric fluid whereas, in the intestinal fluid the drug release was obtained up to 20 days as indicated by in vitro studies. Pharmacokinetic analysis of the data revealed changes in C max; AUCo–α ; t 1/2 (a) and t 1/2 (e) when drugs were given entrapped in PLG microparticles. Higher peak concentration, area under the concentration time curve and delayed elimination rate of entrapped drugs indicated the potential of PLG for effective treatment of tuberculosis. Further, work is being carried out to evaluate the chemotherapeutic efficacy of the antitubercular drugs encapsulated in PLG microspheres.
Keywords: PLG; Oral drug delivery; Antitubercular drugs;
Characterization of alginate/poly-l-lysine particles as antisense oligonucleotide carriers by M. González Ferreiro; L. Tillman; G. Hardee; R. Bodmeier (47-59).
The gel forming characteristics of alginate in the presence of calcium ions and further crosslinking with poly-l-lysine led to the formation of sponge-like nano- and microparticles. The particle size was varied by adjusting the final concentrations of and proportions between the components. The region for particle formation was from 0.04 to 0.08% (w/v) of alginate in the final formulation, the change from the nm to μm size range occurred at a concentration of approx. 0.055% (w/v). Oligonucleotide-loaded microparticles were prepared by two different methods, either by absorption of the drug into the crosslinked polymeric matrix or by incorporation of an oligonucleotide/poly-l-lysine complex into a calcium alginate pre-gel. The release of oligonucleotide from microparticles prepared by the first method was higher. The addition of increasing amounts of poly-l-lysine resulted in larger particles, higher oligonucleotide loading and slower drug release. An increase in the final solid content of the formulation led to larger particles, especially with high concentrated calcium alginate pre-gels. Microparticles based on alginate and poly-l-lysine are potential carriers for antisense oligonucleotides.
Keywords: Alginate; Antisense oligonucleotide; Complexation; Microparticles; Nanoparticles; Poly-l-lysine;
Release of ketoprofen enantiomers from HPMC K100M matrices—diffusion studies by M.A. Solinı́s; Y. de la Cruz; R.M. Hernández; A.R. Gascón; B. Calvo; J.L. Pedraz (61-68).
Sustained release formulations of ketoprofen elaborated with HPMC K100M were studied to test the hypothesis that chiral excipients can stereoselectively affect the release of the racemic drug. The differences observed in the percentage released between enantiomers show the existence of a chiral interaction between ketoprofen and HPMC K100M. HPMC interacts preferably with the S-enantiomer, although the enantioselectivity observed was not relevant from biopharmaceutical and clinical points of view. Diffusion studies were carried out in membrane diffusion cells to simplify the excipient–drug system and hence to analyze only the influence of diffusion process on the stereoselectivity. The results obtained show that the absence of the erosion process strengthens the enantiomeric differences observed in the drug release from tablets. Another objective of this work was to study the influence of formulation pH on the ‘in vitro’ release profile of ketoprofen. The amount and the release mechanism of ketoprofen from formulations elaborated are conditioned mainly by the pH of the matrix.
Keywords: Chiral excipient; Drug diffusion; Stereoselective dissolution; Ketoprofen; Hydroxypropylmethylcellulose K100M;
Continuous twin screw extrusion for the wet granulation of lactose by E.I Keleb; A Vermeire; C Vervaet; J.P Remon (69-80).
The suitability of continuous twin screw extrusion for the wet granulation of α-lactose monohydrate was studied and compared with conventional high shear granulation. The influence of process parameters (screw speed and total input rate) and formulation variables (water and polyvinylpyrrolidone (PVP) concentration) on the properties of granules (yield, particle size distribution, friability and compressibility) and tablets (tablet tensile strength, friability and disintegration time) was investigated. Variation of the formulation and process parameters had a major effect on the process feasibility. Optimization of these parameters is required to allow continuous processing and to ensure a high yield. Total input rate, screw speed and water concentration had a minor influence on the granule and the tablet properties. The addition of PVP had no major influence on the granule properties, but significantly affected the tablet characteristics. For granules formulated with and without PVP a yield above 50%, a friability below 30% and a compressibility below 15% was obtained. Tablets without PVP showed a tensile strength below 0.6 MPa, a friability above 1% and a disintegration time below 3 min, whereas tablets with PVP showed a tensile strength above 0.6 MPa, a friability below 1% and a disintegration time ranging from 8 to 15 min. High shear granulation was only possible when PVP was added and it required a higher amount of water. It was concluded that wet granulation of α-lactose monohydrate using continuous twin screw extrusion is a robust process and might offer a suitable alternative for high shear granulation in the pharmaceutical industry.
Keywords: Granulation; Continuous twin screw extrusion; Granule and tablet properties; High shear granulation; Lactose monohydrate;
Preparation of alginate beads for floating drug delivery system: effects of CO2 gas-forming agents by B.Y. Choi; H.J. Park; S.J. Hwang; J.B. Park (81-91).
Floating beads were prepared from a sodium alginate solution containing CaCO3 or NaHCO3 as gas-forming agents. The solution was dropped to 1% CaCl2 solution containing 10% acetic acid for CO2 gas and gel formation. The effects of gas-forming agents on bead size and floating properties were investigated. As gas-forming agents increased, the size and floating properties increased. Bead porosity and volume average pore size, as well as the surface and cross-sectional morphology of the beads were examined with Mercury porosimetry and Scanning Electron Microscopy. NaHCO3 significantly increased porosity and pore diameter than CaCO3. Incorporation of CaCO3 into alginate solution resulted in smoother beads than those produced with NaHCO3. Gel strength analysis indicated that bead strength decreased with increasing gas-forming agent from 9 to 4 N. Beads incorporating CaCO3 exhibited significantly increased gel strength over control and NaHCO3-containing samples. Release characteristics of riboflavin as a model drug were studied in vitro. Release rate of riboflavin increased proportionally with addition of NaHCO3. However, increasing weight ratios of CaCO3 did not appreciably accelerate drug release. The results of these studies indicate that CaCO3 is superior to NaHCO3 as a gas forming agent in alginate bead preparations. The enhanced buoyancy and sustained release properties of CaCO3-containing beads make them an excellent candidate for floating drug dosage systems (FDDS).
Keywords: Alginate bead; Floating bead; Floating drug dosage system (FDDS); Gas-forming agent; NaHCO3; CaCO3;
A local delivery system for fentanyl based on biodegradable poly(l-lactide-co-glycolide) oligomer by Sun-Ah Seo; Hak Soo Choi; Gilson Khang; John M. Rhee; Hai Bang Lee (93-101).
To obtain a sustained fentanyl delivery with effective and precise control, fentanyl loaded wafer was fabricated using poly(l-lactide-co-glycolide) (PLGA) oligomer by direct compression method. XRD and DSC analysis indicated the presence of crystalline drug in the wafers. The release of fentanyl from PLGA wafer was determined to be primarily diffusion controlled, but swelling and erosion also contributed to the release process. In vitro release studies showed that different release patterns and rates could be achieved by simply modifying factors in the preparation conditions. The wafer degradation profiles were also investigated to understand the drug release mechanism. Gravimetric studies of mass loss of wafers during the incubation revealed that the weight loss increased apparently after 4 days. These results indicate that the polymer degradation was contributed to drug release followed by diffusion. From the results, this constant localized release system can potentially provide anesthesia for a longer period than injection or topical administration.
Keywords: Fentanyl; Poly(l-lactide-co-glycolide); Local delivery; Gravimetric study;
Utilization of supercritical carbon dioxide for complex formation of ibuprofen and methyl-β-cyclodextrin by M. Charoenchaitrakool; F. Dehghani; N.R. Foster (103-112).
The dissolution rate of a drug into the biological environment can be enhanced by forming complexes with cyclodextrins and their derivatives. In this study, ibuprofen–methyl-β-cyclodextrin complexes were prepared successfully by passing ibuprofen-laden CO2 through a methyl-β-cyclodextrin packed bed. The maximum drug loading obtained in this work was 10.8 wt.%, which was comparable to that of a 1:1 complex (13.6 wt.% of ibuprofen). The complex exhibited instantaneous dissolution profiles in water solution. The enhanced dissolution rate was attributed to the amorphous character and improved wettability of the product.
Keywords: Ibuprofen; Methyl-β-cyclodextrin; Supercritical CO2;
Investigation of polymeric nanoparticles as carriers of enalaprilat for oral administration by P. Ahlin; J. Kristl; A. Kristl; F. Vrečer (113-120).
Enalaprilat is a typical angiotensin-converting enzyme inhibitor and is very poorly absorbed from the gastrointestinal tract. The aim of this study was to design and characterize poly-(lactide-co-glycolide) (PLGA) and polymethylmethacrylate (PMMA) nanoparticles containing enalaprilat and to evaluate the potential of these colloidal carriers for the transport of drugs through the intestinal mucosa. Nanoparticle dispersions were prepared by the emulsification–diffusion method and characterized according to particle size, zeta potential, entrapment efficiency and physical stability. Effective permeabilities through rat jejunum of enalaprilat in solution and in enalaprilat-loaded nanoparticles were compared using side-by-side diffusion chambers. The solubility of enalaprilat is very low in many acceptable organic solvents, but in benzyl alcohol is sufficient to enable the production of nanoparticles by the emulsification–diffusion process. The diameters of drug-loaded PMMA and PLGA nanoparticles were 297 and 204 nm, respectively. The concentration of the stabilizer polyvinyl alcohol (PVA) in dispersion has an influence on particle size but not on drug entrapment. The type of polymer has a decisive influence on drug content—7 and 13% for PMMA and PLGA nanoparticles, respectively. In vitro release studies show a biphasic release of enalaprilat from nanoparticle dispersions—fast in the first step and very slow in the second. The apparent permeability coefficient across rat jejunum of enalaprilat entrapped in PLGA nanoparticles is not significantly improved compared with enalaprilat in solution.
Keywords: Nanoparticles; Poly-(lactide-co-glycolide); Ex vivo permeability; Entrapment efficiency; Oral drug delivery;
Preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent diffusion method in aqueous system and physicochemical characterization by F.Q Hu; H Yuan; H.H Zhang; M Fang (121-128).
Solid lipid nanoparticles (SLN) are a colloidal carrier system for controlled drug delivery. Monostearin SLN were prepared by a novel solvent diffusion method in an acidic aqueous system in order to improve the recovery of the method. The lipophilic model drug clobetasol propionate was incorporated to study the recovery of nanoparticles, entrapment efficacy, zeta potential (charge) and drug delivery characterization. The drug and monostearin were dissolved in acetone and ethanol at 50 °C in water bath, the resultant organic solution was poured into an acidic aqueous (pH 1.10) containing 1% polyvinyl alcohol (PVA) under mechanical agitate at room temperature. The drug loaded SLN was quickly produced with an aggregation state and easily separated by centrifugation. The recovery of nanoparticles was markedly increased compared to using a usual aqueous (pH 5.73) containing the same concentration of PVA. After burst drug release at the first 3 h, a distinctly prolonged release over a monitored period of 4 days was observed and nearly 6% drug was released in each day. Further, a novel preparation method and the optimized separation parameters in the present research for SLN were established. These results also demonstrate the principle suitability of SLN as a prolonged release formulation for lipophilic drugs.
Keywords: Solvent diffusion method in aqueous system; Solid lipid nanoparticles; Clobetasol propionate; Monostearin; Entrapment efficacy; Prolonged release;
Estimation of intradermal disposition kinetics of drugs: II. Factors determining penetration of drugs from viable skin to muscular layer by Kazutaka Higaki; Masahide Asai; Takayuki Suyama; Kazuki Nakayama; Ken-ichi Ogawara; Toshikiro Kimura (129-141).
To develop a more efficient transdermal delivery system, it is very important to regulate the intradermal disposition of drugs after topical application. We tried to elucidate the factors determining the intradermal disposition kinetics, especially drug penetration from the viable skin to the muscular layer, mainly based on the six-compartment model, including the contralateral skin and muscle for ten model drugs with different physicochemical characteristics. In vivo transdermal absorption study was performed for six model drugs using the stripped-skin rats. The fitting analyses by the six-compartment model gave the theoretical curves describing the observed data very well and the reasonable pharmacokinetic parameters, showing the pharmacokinetic model should be useful for the estimation of the intradermal disposition kinetics of drugs applied topically again. The simulation study using the pharmacokinetic parameters obtained above could show the relative contribution of the direct penetration and the distribution from the systemic circulation to the muscular distribution of drugs. The largest contribution of direct penetration was observed for antipyrine (90.8%) and the smallest was for felbinac (43.3%). Among the pharmacokinetic parameters obtained above, the clearance from the viable skin to the muscle (CL vs–m) was found to be significantly correlated with the unbound fraction of drugs in the viable skin (fu vs). Although the clearance from the viable skin to the plasma (CL vs–p) also tended to increase as fu vs increased, the ratio of CL vs–m to CL vs–p was significantly correlated with fu vs, meaning that the larger amount of unbound drug in the viable skin significantly contributes to the direct penetration into the muscle more than to the systemic absorption. On the other hand, k direct values obtained in in vitro penetration study—the penetration rate constant of drugs from the viable skin to the muscular layer—were found to be correlated with CL vs–m values for seven model drugs. Therefore, adding the in vitro experiments for the other three model drugs, the multiple linear regression analysis of k direct was performed for ten model drugs in terms of fu vs, logarithm of the partition coefficient (Log P) and molecular weight. The results clearly showed the largest and significant contribution of fu vs to the direct penetration of drugs from the viable skin to the muscular layer, indicating that a drug with the higher value of fu vs in the viable skin can penetrate more into the muscular layer.
Keywords: Intradermal disposition; Unbound fraction; Multiregression analysis; Penetration into muscular layer; Systemic absorption; Distribution from systemic circulation;
Characterisation of the mechanical properties of polymer films formed from aqueous polymer dispersions by creep testing by S.V. Lafferty; J.M. Newton; F. Podczeck (143-148).
The mechanical properties of films formed from an aqueous dispersion of polymethlymethacrylate (Eudragit NE30D) and as mixture with an aqueous dispersion of ethylcellulose (Aquacoat ECD30), have been assessed by applying creep tests at different temperatures, using a dynamic mechanical analyser. In the region of linear creep, the film prepared from 100% Eudragit was far less elastic than when 60% Aquacoat was present. In this region, when the applied stress was doubled, the strain response was doubled. In the non-linear region of behaviour, there is clear evidence that the mixed film is more elastic than the film containing only Eudragit.
Keywords: Aquacoat ECD30; Creep test; Dynamic mechanical analysis; Eudragit NE30D;
Clickhaler® dry powder inhaler: focussed in vitro proof of principle evaluation of a new chemical entity for asthma by Roch Thibert; Mark Parry-Billings; Martin Shott (149-156).
A new chemical entity (NCE) was evaluated in the Clickhaler® (Innovata Biomed Ltd.) dry powder inhaler, a reservoir-based multidose delivery system. The standard device metering system was modified to handle higher doses (nominally 20 mm3 of lactose based blend). The micronized drug was formulated at 12.5% w/w in lactose monohydrate (Pharmatose 325M, DMV) equivalent to a nominal dose of approximately 1 mg. Delivered shot weight (mg of blend) and emitted dose (μg drug) averaged 7.4 mg and 905 μg, respectively, and were consistent (within ±20 to 25% of mean) through the life of the inhaler. The fine particle fraction (FPF) (Andersen cascade impactor) was typically 60%. A short stability study (i.e. 3 months at room temperature, 53 or 75% RH, unpacked) showed that the in vitro performance was maintained. The results of these studies provide in vitro proof of principle for this novel drug/device combination.
Keywords: Dry powder inhaler; Asthma; Aerosol;
Modelling partitioning of sparingly soluble drugs in a two-phase liquid system by Mario Grassi; Nicoletta Coceani; Lorenzo Magarotto (157-169).
The aim of this work was to develop a proper mathematical model able to describe the kinetics partitioning of a drug between a polar (water buffer) and an apolar (n-octanol) liquid phase. In particular, attention is focussed on sparingly soluble drugs in one or both environments. Basically, we suppose that drug fluxes occurring between the polar and apolar phase depend also on drug solubility, and not only on both the kinetics constants and the instantaneous drug concentration in the two phases. The proposed model adequately describes the drug partitioning of sparingly water soluble drugs (piroxicam and nimesulide) as proven by the comparison of the predicted and experimental data. Moreover, it indicates the unsuitability of a previous approach (Chem. Pharm. Bull. 29 (1961) 2718) in describing the partitioning kinetics unless sink conditions in both phases are attained, this being difficult to achieve when working with sparingly soluble drugs. Consequently, the model represents a simple and reliable tool to study the drug partitioning kinetics.
Keywords: Mathematical modelling; Partition coefficient; Sparingly soluble drug;
The influence of pellet shape and surface properties on the drug release from uncoated and coated pellets by Ranjana Chopra; Göran Alderborn; Fridrun Podczeck; J.Michael Newton (171-178).
Pellets of different shape, varying from spherical to cylindrical, without and with film coating were tested for their drug release properties. For non-disintegrating uncoated pellets, drug release was found to be inversely related to the pellet porosity. A change of 5% in porosity doubled the value of the mean dissolution time (MDT). As coat thickness increased, the MDT value of coated pellets increased. For those pellets, which are nearly spherical, once a thickness of about 20 μm had been achieved, there was little further reduction in retardation. Pellets produced by extrusion/spheronisation appeared to prolong drug release to a larger extent than those where the extrusion step had been omitted. There was a strong inverse relationship between the surface area by volume of the coated pellets and the value of the MDT. The values of the relative dispersion coefficient (RD), which is an indicator of the drug release mechanism, were related to the amount of fluid used to manufacture the pellets and the pellet shape, in a similar fashion for both uncoated and coated pellets. This suggested that the presence of the film coating changed the rate but not the mechanism of drug release.
Keywords: Drug release; Film coating; Mean dissolution time; Pellet porosity; Pellet shape; Pellet surface area; Relative dispersion coefficient;
Kinetic examination of the mechanical transition of polymethyl methacrylate films prepared from aqueous dispersions by S.V. Lafferty; J.M. Newton; F. Podczeck (179-183).
The activation energy of the phase transition of cast polymethyl methacrylate films produced from an aqueous dispersion (Eudragit NE30D) has been estimated from Dynamic Mechanical Thermal Analysis. The value was found to lie between 170 and 350 kJ mol−1, the variation arising from the different specimen test geometry and testing conditions. From experiments conducted at a range of frequencies and temperatures it was found possible to utilise the concept of frequency shift to produce a master curve, which could relate viscoelastic properties over the temperature range of 5–55 °C and a frequency range of 0.1 to 50 Hz.
Keywords: Activation energy; Dynamic mechanical thermal analysis; Phase transition; Polymethyl methacrylate dispersions (Eudragit NE 30D);
Optimized chemical structure of nanoparticles as carriers for oral delivery of salmon calcitonin by Shinji Sakuma; Norio Suzuki; Rika Sudo; Ken-ichiro Hiwatari; Akio Kishida; Mitsuru Akashi (185-195).
Nanoparticles having two kinds of surface hydrophilic polymeric chains were prepared by the free radical copolymerization between styrene and hydrophilic macromonomers terminating in vinylbenzyl groups. Their potential as carriers for oral peptide delivery was investigated using salmon calcitonin (sCT) in rats. After oral administration of mixtures of sCT and nanoparticles, the ionized calcium concentration in blood was measured. The absorption of sCT was significantly enhanced by nanoparticles having poly-N-isopropylacrylamide (PNIPAAm) chains on their surfaces. This enhancement effect was considerably increased by introducing cationic poly-vinylamine (PVAm) groups to the surface of PNIPAAm nanoparticles. The absorption enhancement depended on the ratio of NIPAAm and VAm macromonomers to styrene in the nanoparticle preparation. In contrast, the introduction of nonionic poly-vinylacetamide (PNVA) groups eliminated completely the absorption-enhancing function of PNIPAAm nanoparticles. It was suggested that this disappearance was due to the shielding of PNIPAAm groups by PNVA groups. The enhancement effect of sCT absorption by nanoparticles was greatly dominated by their chemical structure that was closely related to surface characteristics. Optimization of the chemical structure on the basis of the mechanism of the absorption enhancement resulted in the further improvement of sCT absorption.
Keywords: Nanoparticle; Macromonomer; Graft copolymer; Oral delivery; Peptide; Salmon calcitonin;
An in vitro evaluation of a chitosan-containing multiparticulate system for macromolecule delivery to the colon by Hua Zhang; Ibrahim A. Alsarra; Steven H. Neau (197-205).
A multiparticulate system of chitosan hydrogel beads has been investigated for colon-specific delivery of macromolecules using fluorescein isothiocyanate–labeled bovine serum albumin as a model protein. The hydrogel bead was formed by polyelectrolyte complexation of chitosan with its counterion, tripolyphosphate (TPP). The protein release experiments were carried out in vitro under different conditions to simulate the pH and times likely to be encountered during intestinal transit to the colon. The results show that the hydrogel beads were degraded by rat cecal and colonic enzymes, resulting in a marked acceleration in the release of protein. The ability of rat cecal and colonic enzymes to degrade chitosan hydrogel beads was independent of pretreatment conditions. A commercial beta-glucosidase preparation containing a chitinase did not have a similar effect on the chitosan bead, even though it has been found to mimic the degradation function of rat cecal and colonic enzymes in vitro for chitosan in solution. Degradation of the chitosan–TPP hydrogel beads in the presence of rat cecal and colonic enzymes indicates the potential of this multiparticulate system to serve as a carrier to deliver macromolecules specifically to the colon.
Keywords: Chitosan; Colon-specific drug delivery; Hydrogel beads; Multiparticulates; Rat microbial enzymes; Almond emulsin beta-glucosidase;
Preformulation studies of a novel camptothecin anticancer agent, CKD-602: physicochemical characterization and hydrolytic equilibrium kinetics by Jae-Hyun Kim; Seok-Kyu Lee; Jong-Lae Lim; Hee-Jong Shin; Chung Il Hong (207-211).
(20S)-7-(2-isopropylamino)ethylcamptothecin·HCl (CKD-602), a new camptothecin (CPT) anticancer agent, is a pale yellowish crystalline compound. DSC thermogram exhibited a melt endotherm near 270 °C, and CKD-602 was found to be slightly hygroscopic. The solubility of CKD-602 in deionized water was 8.22 mg/ml, and two pK a values were measured to be 2.32 and 9.15, respectively. A pH-dependent partition coefficient behavior in octanol-buffer was observed. CKD-602 in solid state was stable over the range of temperature and humidity, but decomposed slightly by light. The hydrolysis of CKD-602 occurred reversibly and rapidly in aqueous buffer solutions. The conversion rate constants (k f: from the lactone to the carboxylate and k r: from the carboxylate to the lactone) and the final equilibrium ratio (K eq) between two species were dependent on the pH of aqueous solutions.
Keywords: Preformulation; (20S)-7-(2-isopropylamino)ethylcamptothecin HCl; Anti-cancer agent; pH-dependent partition coefficient; Reversible hydrolysis;