European Journal of Pharmaceutics and Biopharmaceutics (v.64, #2)

APV Diary (S1-S3).

Microencapsulation of Streptococcus equi antigens in biodegradable microspheres and preliminary immunisation studies by Ana F. Azevedo; Jorge Galhardas; António Cunha; Patrícia Cruz; Lídia M.D. Gonçalves; António J. Almeida (131-137).
Streptococcus equi subspecies equi is the causative agent of strangles, a bacterial infection of the respiratory tract of equidae. Current strategies to prevent strangles rely on antimicrobial therapy or immunisation with inactivated bacteria, S. equi bacterin, or M-like protein (SeM) extract. The aim of this work was to investigate whether immunisation with whole killed S. equi or a bacterial lysate entrapped in poly(lactide-co-glycolide) (PLGA) microspheres might induce protective immunity to mice. Animals were treated with a dose of antigen equivalent to 25 μg of SeM. For intranasal route animals were primed on days 1, 2 and 3 and were boosted on day 29. For intramuscular route, primary immunisation was carried out with a single injection on day 1 and animals were boosted on day 29. On day 43 animals were submitted to a challenge with a virulent strain of S. equi. Vaccination with antigen-containing microspheres induced higher serum antibody levels in mice treated by the intranasal route, whereas intramuscular immunisation did not reveal any difference between control and treatment groups. Microencapsulated antigens achieved to fully protect mice against experimental infection irrespective of the route of administration used. Following intranasal or intramuscular administration soluble antigen failed to protect mice against challenge. These studies indicate that PLGA microspheres are a potential carrier system for the delivery of S. equi antigens.
Keywords: Microspheres; Mucosal delivery: Poly(lactide-co-glycolide); Strangles; Vaccine;

Nasal immunization studies using liposomes loaded with tetanus toxoid and CpG-ODN by Mohsen Tafaghodi; Mahmood-Reza Jaafari; Sayyed Abolghasem Sajadi Tabassi (138-145).
To increase the systemic and mucosal immune responses against the nasally administered tetanus toxoid, liposomes as a drug delivery system and CpG-ODN as an adjuvant were evaluated. Rabbits were nasally immunized with entrapped tetanus toxoid (TT) and CpG-ODN in neutral liposomes and systemic and mucosal immune responses were determined. Liposomes containing TT and CpG-ODN were prepared by dehydration–rehydration method. The volume mean diameter of liposomes was 2.3 ± 0.6 μm. Encapsulation efficiency of TT and CpG-ODN was determined as 54.0 ± 8.8 and 60.1 ± 7.4, respectively. The leakage of the encapsulated TT from liposomes reached 7.38% after 3 months. Encapsulated TT kept its intact structure, and its immunoreactivity was also completely preserved, as shown by SDS–PAGE and ELISA methods. The highest serum IgG and antitoxin titers were observed in groups immunized with solution formulations (P  < 0.001). However the highest mucosal sIgA titers were achieved by liposomes encapsulated with TT. CpG-ODN as an adjuvant was able to increase the serum IgG and antitoxin titers when co-administered with TT solution (P  < 0.05) or co-encapsulated with TT in liposomes (P  < 0.01), but failed to increase the sIgA titers in nasal lavages. No hemolysis occurred on incubation of liposomes and human RBCs. Also after nasal administration of plain liposomes to human volunteers, no local irritation was seen. Intranasal administration of liposomes encapsulated with vaccines showed to be an effective way for inducing the mucosal immune responses.
Keywords: Nasal immunization; Neutral liposome; CpG-ODN; Tetanus toxoid; Adjuvant; Antitoxin; sIgA; IgG;

The main objective of this work was to investigate the complexation mechanism of the tripeptide glutathione with α-cyclodextrin (α-CyD). The final purpose was to explore the possibility of using this complexation approach for preserving the stability of this peptide in all biological environments relevant for oral drug delivery. The complexes between the peptide and α-CyD were formed in aqueous solution and the complexation mechanism was investigated using different 1H NMR experimental approaches. The resulting complexes were also studied with respect to their ability to protect the peptide against proteolytic degradation by the exopeptidase, γ-glutamyltranspeptidase. The NMR experiment, 1D-saturation transfer NOE difference (STD), evidenced the interaction between α-CyD and glutathione. The binding constants, calculated by a titration method, were in the range of 55–70 M−1 at 25 °C and in the range 68–72 M−1 at 37 °C. Moreover, from the 1D-pulse field gradient spin echo-transverse-rotating frame nuclear Overhauser (PFGSE-T ROESY) spectra it was concluded that α-CyD binds preferably to the l-glutamate (side chain) moiety of glutathione, leaving the glycine residue exposed to the external medium. This result was consistent with those of the in vitro stability study, which indicated that the degradation of glutathione was markedly reduced to the half in 2 h upon inclusion in α-CyD. Overall, these results show the possibility of protecting specific peptide groups by their inclusion in CyDs as well as the utility of NMR experiments for the understanding of this stabilization strategy.
Keywords: Cyclodextrins; Glutathione; Inclusion complex; Nuclear magnetic resonance; Peptide stability;

Nanoencapsulation of usnic acid: An attempt to improve antitumour activity and reduce hepatotoxicity by Noemia Pereira da Silva Santos; Silene Carneiro Nascimento; Marcela Silvestre Outtes Wanderley; Nicodemos Teles Pontes-Filho; José Figueiredo da Silva; Célia Maria Machado Barbosa de Castro; Eugênia Cristina Pereira; Nicácio Henrique da Silva; Neli Kika Honda; Nereide Stela Santos-Magalhães (154-160).
Despite the recognised antiproliferative and antitumour properties of usnic acid, its therapeutic application has yet to be introduced. In fact, the high hepatotoxicity and low water solubility of usnic acid have somewhat restricted its practical use in anticancer therapy. The aim of this study was therefore to investigate the antitumour activity of usnic acid encapsulated into nanocapsules prepared with lactic co-glycolic acid polymer. Usnic acid-loaded nanocapsules were obtained using the interfacial deposition of a preformed polymer. The antitumour activity was confirmed on an ascitic tumour (Sarcoma-180) implanted in Swiss mice and estimated by means of the tumour inhibition. The results of antitumour activity confirmed that the encapsulation of usnic acid into PLGA-nanocapsules produced a 26.4% increase in tumour inhibition as compared with the standard free usnic acid treatment. Vacuolization of hepatocytes and a mild lymphocytic infiltration in portal spaces were observed in animals treated with free usnic acid. However, this hepatotoxicity was substantially reduced when animals were treated with usnic acid-loaded nanocapsules. No histological changes were noticed in the kidneys or spleen of animals treated either with usnic acid or usnic acid-loaded nanocapsules. These results suggest that nanoencapsulation may be a way of enabling usnic acid to be used in chemotherapy.
Keywords: Usnic acid; Cladonia substellata; Nanocapsules; Antitumour activity; Toxicity;

Feasibility of simple chitosan sheet as drug delivery carrier by Kieko Saito; Takuya Fujieda; Hisashi Yoshioka (161-166).
Chitosan, a biodegradable and biocompatible polysaccharide, is a potentially useful material in various fields. We developed a simple chitosan sheet and examined the possibility of using an adriamycin-containing chitosan sheet as a drug carrier for controlled release. To prepare a carrier consisting only of chitosan, a chitosan suspension was subjected to acid-alkaline treatment, mixed with adriamycin, frozen and freeze-dried. The adriamycin-containing chitosan sheet was inserted into the peritoneal cavity of mice in order to investigate its biodegradation. The appearance of decomposition of chitosan was observed using scanning electron microscopy, and adriamycin in urine and liver was detected for 1 and 2 weeks, respectively. Adriamycin metabolites were detected in plasma for 2 weeks. Furthermore, adriamycin remained in the chitosan sheet without being metabolized after 2 months. These results suggested that the chitosan sheet prepared in this study might improve therapeutic efficacy in topical lesions as a carrier of sustained-release drugs.
Keywords: Chitosan; Drug carrier; Adriamycin; Biodegradation; Biomaterials; Controlled release;

Liquid boundary movements in cylindrical and convex hydrophobic matrix tablets: Effects on tablet cracking and drug release by Jari Pajander; Bert van Veen; Ossi Korhonen; Reijo Lappalainen; Jarkko Ketolainen (167-172).
The aim of this study was to investigate liquid penetration into both cylindrical and convex hydrophobic matrix tablets and to relate the changes in tablet structure to drug release. Starch acetate with degree of substitution of 2.7 was used as a hydrophobic matrix former and anhydrous caffeine as a freely soluble model drug. Phenolred was used as a colouring agent to enhance the visual detection of the liquid boundary movements, which were examined in axial and radial directions for both types of tablets. The tablets started to expand during the dissolution, resulting in cracking as the liquid boundary penetrated into tablet. The cracking influences drug release by shortening the diffusion path and decreasing the tortuosity. The liquid boundaries proceed differently in cylindrical and convex tablets, this being attributable to differences in pore structure and density distribution. Cylindrical tablets are quite homogeneous in terms of density, but convex tablets have more porous areas at the domes of the tablet.
Keywords: Hydrophobic matrix; Tablet; Starch acetate; Liquid boundary; Tablet cracking; Drug release;

The objective of this study was to develop a rupturable, capsule-based pulsatile drug delivery system with pH-independent properties prepared using aqueous coating. The drug release is induced by rupturing of the top-coating, resulting by expanding of swellable layer upon water penetration through the top-coating.Croscarmellose sodium (AcDiSol®) is a preferable superdisintegrant compared to low substituted hydroxypropylcellulose (L-HPC) and sodium starch glycolate (Explotab®), because of controlled lag time, followed by a quick and complete drug release. However, due to its anionic character, AcDiSol® showed pH-dependent swelling characteristics (pH 7.4 >0.1 N HCl) resulting in a pH-dependent lag time. The pH dependency could be eliminated by the addition of fumaric acid to the swelling layer, which allowed to keep an acidic micro-environment.Formation of the rupturable top-coating was successfully performed using an aqueous dispersion of ethylcellulose (Aquacoat® ECD), whereby sufficient drying during the coating was needed to avoid swelling of the AcDiSol® layer. A higher coating level was required, when aqueous dispersion was used, compared to organic coatings. However, an advantageous aspect of the aqueous coating was the lower sensitivity of the lag time to a deviation in the coating level.
Keywords: pH independent; Pulsatile drug release; Superdisintegrants; AcDiSol®; Ethylcellulose; Aquacoat® ECD; Hard gelatin capsule;

A method for the preparation of monolithic osmotic pump tablet was obtained by coating the indented core tablet compressed by the punch with a needle. Atenolol was used as the model drug, sodium chloride as osmotic agent and polyethylene oxide as suspending agent. Ethyl cellulose was employed as semipermeable membrane containing polyethylene glycol 400 as plasticizer for controlling membrane permeability. The formulation of atenolol osmotic pump tablet was optimized by orthogonal design and evaluated by similarity factor (f 2). The optimal formulation was evaluated in various release media and agitation rates. Indentation size of core tablet hardly affected drug release in the range of (1.00–1.14) mm. The optimal osmotic tablet was found to be able to deliver atenolol at an approximately constant rate up to 24 h, independent of both release media and agitation rate. The method that is simplified by coating the indented core tablet with the elimination of laser drilling may be promising in the field of the preparation of osmotic pump tablet.
Keywords: Atenolol; Monolithic osmotic pump tablet; Orthogonal design; Similarity factor; Indented tablet;

In this study, metformin hydrochloride (MH) sustained-release pellets were successfully prepared by centrifugal granulation. Seed cores preparation, drug layering, talc modification and coating of polymeric suspensions were carried out in a centrifugal granulator. Talc modification was performed before coating in order to overcome the high water solubility of metformin. The influence of surface modification by talc, the effects of Eudragit® types and ratios, as well as the correlation between in vitro release and in vivo absorption were investigated in detail. Experimental results indicated that talc modification made a decisive contribution to controlling the drug release by avoiding drug dumping. Three dissolution media: 0.1 M HCl, distilled water and pH 6.8 phosphate buffer were employed to determine the in vitro release behaviors of the above metformin hydrochloride pellets. The relative bioavailability of the sustained-release pellets was studied in 12 healthy volunteers after oral administration in a fast state using a commercially available immediate release tablet (Glucophage) as a reference. Following coating with a blend of Eudragit® L30D-55 and Eudragit® NE30D (1:20), at 7% or 10% coating level, respectively (referred to as F-2, F-3), the pellets acquired perfect sustained-release properties and good relative bioavailability. The C max, T max and relative bioavailability for F-2 and F-3 coated pellets were 1.21 μg/ml, 6 h, 97.6% and 1.65 μg/ml, 8 h, 165%, respectively. Combined use of two Eudragit® polymers with different features as coating materials produced the desired results. Restricted delivery of metformin hydrochloride to the small intestine from differently coated pellets resulted in increased relative bioavailability and a sustained release effect. The adoption of several different pH dissolution media established a better relationship between the in vitro release and in vivo absorption of the sustained-release pellets.
Keywords: Sustained-release pellets; Centrifugal granulation; Metformin hydrochloride; Eudragit® L30D-55; Eudragit® NE30D;

Agglomeration tendency in dry pharmaceutical granular systems by Emilie DesRosiers Lachiver; Nicolas Abatzoglou; Louis Cartilier; Jean-Sébastien Simard (193-199).
The agglomeration tendency of dry pharmaceutical mixtures containing various concentrations of Xylitab®100 (Xylitol), calcium carbonate precipitated (CCP) and magnesium stearate (MgSt) was evaluated statistically as a function of mixing time. A Ro-Tap tester was employed to mix the three pharmaceutical components, and the agglomerates formed were measured with respect to their weight and size. An experimental design was devised and applied to structure and then statistically analyze the results.Xylitab was found not to be influential in the formation of agglomerates, but aided in deagglomeration when mixed with other components. CCP and MgSt formed agglomerates over time and showed positive interactions favouring agglomeration. The agglomerates started to fracture when they reached a critical size, at which stage the particles’ attraction forces (cohesion forces) were weaker than both gravity and inertia.It has been shown and quantitatively demonstrated that the mixing time and ingredient concentrations of a three-component pharmaceutical mixture can affect agglomeration tendency.
Keywords: Agglomeration; Powder; Granular systems; Mixing; Flow; Lubricant;

Preparation of a solid dispersion of felodipine using a solvent wetting method by Eun-Jung Kim; Myung-Kwan Chun; Jae-Sang Jang; In-Hwa Lee; Kyeo-Re Lee; Hoo-Kyun Choi (200-205).
A straightforward solvent wetting method was used to prepare felodipine solid dispersions in the presence of various carriers. Dichloromethane is not needed when HPMC solid dispersions were produced using the solvent wetting method. The amount of ethanol used to prepare solid dispersions did not have a significant effect on the dissolution rate of felodipine. The results of X-ray diffraction and thermal analysis indicated that the drug was in the amorphous state when PVP, HPMC, and poloxamer were used as carriers. The dissolution rates of felodipine in PVP, HPMC, or poloxamer solid dispersions were much faster than those for the corresponding physical mixtures. However, dissolution profiles were found to depend on the carrier used; the dissolution rate of felodipine increased slowly for solid dispersions prepared using HPMC, whereas rapid initial dissolution rates were observed for solid dispersions prepared using PVP or poloxamer. Increases in dissolution rates were partly dependent on the ratios of felodipine to carrier. No significant changes in crystal form were observed by X-ray diffraction or thermal analysis, and no significant changes in dissolution rate were observed when sorbitol and mannitol were used as carriers.
Keywords: Felodipine; Solid dispersion; Solvent wetting method; Dissolution; Poorly water-soluble;

The apparent plasticizing effect of polyethylene glycol (PEG) on the crystallinity of spray dried lactose/PEG composites by Kristina Mosén; Kjell Bäckström; Kyrre Thalberg; Torben Schaefer; Anders Axelsson; Henning G. Kristensen (206-211).
Aqueous solutions of lactose and polyethylene glycol (PEG) were spray dried in a Büchi Model 191 spray dryer with the aim to investigate the effect of PEG on the crystallinity of the composite. A PEG concentration of 10.7% by weight of solids was studied for PEG 200, 600, 1500, 4000 and 8000. For PEG 200 and 4000 additional concentrations from 1.5–19.3% to 1.5–32.4%, respectively, were investigated. The spray dried composites were analysed with X-ray powder diffraction and modulating differential scanning calorimetry. The crystallinity of lactose in the composites varied from 0% to 60%, dependent on the molecular weight and concentration of PEG. Apparently, lactose crystallinity is promoted by low molecular weight and high concentration of the PEG. PEG did not affect the lactose glass transition temperature. It is suggested that lactose and PEG are solidified separately during spray drying and that partial crystallization of lactose is associated with effects of PEG on the rate of drying.
Keywords: Spray drying; Polyethylene glycol; Lactose; Glass transition temperature; Crystallinity;

Cefdinir: A comparative study of anhydrous vs. monohydrate form by Walter Cabri; Paolo Ghetti; Marco Alpegiani; Giovanni Pozzi; Angel Justo-Erbez; José Ignacio Pérez-Martínez; Rosario Villalón-Rubio; M. Carmen Monedero-Perales; Angel Muñoz-Ruiz (212-221).
Anhydrous cefdinir (AC) vs. monohydrated cefdinir (MHC) was compared in order to be used as antimicrobial in therapeutics. Different techniques have been used to characterize physically AC and MHC, and also a complete microstructural analysis of raw materials was carried out. Cefdinir and Maltodextrin QDM® 500 (3:2) formulations were compressed in order to obtain tablets with typical dose of Cefdinir, i.e. 300 mg. Dissolution profiles were obtained for both AC and MHC tablets. Finally tablet X-ray diffraction was performed to ensure the stability of the monohydrated form after tabletting being clearly different in both AC and MHC crystals. AC crystal structure was agreed with the known pattern of anhydrous Cefdinir described in the literature. Microstructural analysis showed large differences in specific surface area (SSA), confirmed by mercury intrusion. Crystal structures of both AC and MHC were stable under mixing, compression and storing processes. Dissolution profiles were faster for hydrate form, probably related to microstructural properties of the crystal which remained after tabletting. In conclusion, it is possible to isolate Cefdinir in two forms anhydrous and monohydrate, well characterized and differentiated. The use of this later improves dissolution of tablet dosage form due to the lack of interconversion during tablet manufacture.
Keywords: Cefdinir; Tablets; X-ray diffraction; Dissolution profiles; Microstructural analysis;

In vitro studies on release and human skin permeation of Australian tea tree oil (TTO) from topical formulations by Jürgen Reichling; Uwe Landvatter; Heike Wagner; Karl-Heinz Kostka; Ulrich F. Schaefer (222-228).
Essential oils are widely used in pharmaceutical and cosmetic preparations e.g. as fragrance, active ingredient or penetration enhancer. However, reports on skin absorption are rare. Therefore, the aim of our study was to investigate the capability of terpinen-4-ol, the main compound of Australian tea tree oil (TTO), to permeate human skin. In static Franz diffusion cells permeation experiments with heat separated human epidermis were carried out using infinite dosing conditions and compared to liberation experiments. The flux values of three different semisolid preparations with 5% TTO showed the rank order semisolid O/W emulsion (0.067 μl/cm2  h) > white petrolatum (0.051 μl/cm2  h) > ambiphilic cream (0.022 μl/cm2  h). In comparison to the flux value obtained with the native TTO (0.26 μl/cm2  h), the flux values are remarkably reduced due to the lower amount of terpinen-4-ol. P app values for cream (2.74 ± 0.06 × 10−7  cm/s) and native TTO (1.62 ± 0.12 × 10−7  cm/s) are comparable whereas white petrolatum (6.36 ± 0.21 × 10−7  cm/s) and semisolid O/W emulsion (8.41 ± 0.15 × 10−7  cm/s) demonstrated higher values indicating a penetration enhancement. No relationship between permeation and liberation was found.
Keywords: Tea tree oil; Franz diffusion cell; Human heat-separated epidermis; Drug liberation; Drug permeation; Terpinen-4-ol;

Comparison of permeation enhancing strategies for an oral factor Xa inhibitor using the Caco-2 cell monolayer model by Carsten Bruesewitz; Adrian Funke; Urte Kuhland; Torsten Wagner; Ralph Lipp (229-237).
FXai, a direct inhibitor of the clotting factor Xa, provides high water solubility but poor membrane permeability due to multiple sites of ionization and a molecular weight exceeding 500 Da, making it a Class III drug according to the Biopharmaceutics Classification System. To overcome the ionization problem and increase the transcellular permeability, various ester and hydroxyamidine prodrugs exhibiting a reduced number of ionization sites were studied in the Caco-2 monolayer model for intestinal permeation. Alternatively, the potential transcellular permeation enhancement of Imwitor® 742 and the potential paracellular enhancement of three chitosan formulations were investigated in the same model. FXai has an apparent permeability (P app) of about 1 nm/s, which is generally regarded as very low. The butylester-hydroxyamidine double-prodrug was found to provide a markedly increased permeability (40.4 nm/s) as did the co-application of chitosan (43.3 nm/s). Other prodrugs slightly increased permeability (1.3–9.2 nm/s) but were inferior to the previous attempts to enhance permeability while the Imwitor® admixture showed no effect (1.1 nm/s). Moreover, a bioactivating metabolism towards the hydroxyamidine mono-prodrug was detected in the Caco-2 cell permeation model. Although esterases were overexpressed and mainly located apically, an acceptable permeation was reached. In addition, the prodrugs triggered an efflux system that is not inhibited by verapamil but by quinidine, suggesting the involvement of an organic cation transporter.
Keywords: Factor Xa inhibitor; Caco-2 cell culture; Efflux transporter; Chitosan; Intestinal permeability; Prodrugs; BCS class III drug;

This study described distribution characteristics of olamufloxacin (HSR-903) in lung epithelial lining fluid (ELF) and alveolar macrophage (AM) in rats, two important representative infectious sites in lower respiratory tract infections. The rats were orally administered at a dose of 10 mg/kg. At each designated time, rats were sacrificed, and blood samples were collected from the superior vena cava, and ELF and AM samples were gathered by the bronchoalveolar lavage method. The AUC ratios of ELF/plasma and AM/plasma of HSR-903 were 3.03 ± 0.54 and 97.5 ± 24.2, respectively, notably higher than those of ciprofloxacin (CPFX). Kinetic analyses of concentration–time profiles of HSR-903 in ELF and AM indicated that the influx clearance from plasma to ELF across the alveolar barrier was 5.8-fold higher than the efflux clearance from ELF. Furthermore, the permeability of HSR-903 across the cultured AM plasma membrane was 5.5 and 14.5 times greater than those of CPFX and pipemidic acid (PPA), respectively. A significant correlation (r 2  = 0.995) was achieved between permeability across AM plasma membrane and hydrophobicity, implying that passage through AM membrane was principally involved in the passive diffusion. The extent of AM intracellular binding was the greatest for grepafloxacin, followed by HSR-903, CPFX, levofloxacin and PPA. In conclusion, HSR-903 distributed more efficiently in ELF and AM than CPFX, and the high accumulation of HSR-903 by AM cells may be accounted for by both the high transferability across the AM membrane and avid binding to the membrane phospholipids.
Keywords: Olamufloxacin (HSR-903); Alveolar barrier; Alveolar macrophage; Membrane transport; Phospholipid binding;

Nasal absorption of metoclopramide from different Carbopol® 981 based formulations: In vitro, ex vivo and in vivo evaluation by Cetin Tas; Cansel Kose Ozkan; Ayhan Savaser; Yalcin Ozkan; Umut Tasdemir; Hikmet Altunay (246-254).
There is a need for nasal drug delivery of metoclopramide HCI (MTC) in specific patient populations where the use of commercially available intravenous and oral dosage forms may be inconvenient and/or unfeasible. In this perspective, nasal dosage forms (solution, gel and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer Carbopol 981 (CRB 981). The drug release studies of formulations were performed by using a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. After the ex vivo experiments, the morphological appearances of the nasal mucosa were analyzed with the light microscopic studies. In vivo experiments were carried on sheep model. The release of MTC from solution and powder formulations was found higher than gel formulation (p  < 0.05) and no severe damage was found on the integrity of nasal mucosa after ex vivo experiments. The penetration enhancing effect of dimethyl-β-cyclodextrin (DM-β-CD) used in powder formulations was observed in ex vivo and in vivo experiments. In contrast to in vitro and ex vivo experiments the nasal bioavailability of gel formulation was found higher than those of the solution and powder (p  < 0.05) and might represent a promising novel tool for the systemic delivery of MTC.
Keywords: Nasal drug delivery; Metoclopramide; Carbopol 981; Sheep; Powder; DM-β-CD;

Investigation on physicochemical and biological differences of cefpodoxime proxetil enantiomers by Vasu Kumar Kakumanu; Vinod Arora; Arvind K. Bansal (255-259).
Cefpodoxime proxetil (CP) is a prodrug of cefpodoxime acid (CA), and is supplied as racemic mixture of R- and S-enantiomers. CP has only 50% absolute bioavailability, and the reasons responsible for low bioavailability remain poorly understood. The present work ascertains physicochemical and biological properties of individual isomers of CP and explores their capacity to optimize delivery of CP. Both isomers showed similar pH stability behavior, but R-isomer was more susceptible to enzymatic metabolism compared to S-isomer, when incubated with enzymes collected from various segments of GIT. Based on the in vitro and in vivo results, use of S-isomer for development of a dosage form such as gastro-retentive dosage form can improve oral bioavailability of CP.
Keywords: Cefpodoxime proxetil; Enantiomers; Differences; Enzymes; Segments; Regional metabolism; GIT; Physicochemical; Biological;