F. Veiga

Inclusion complexation of tolbutamide with β-cyclodextrin and hydroxypropyl-β-cyclodextrin

Inclusion complexes of tolbutamide with β-cyclodextrin and hydroxypropyl-β-cyclodextrin were prepared using different methods: kneading, coprecipitation and freeze-drying. Inclusion complexation in aqueous solution and in solid phase state was studied by the solubility method, X-ray diffractometry, thermal analysis and Raman spectroscopy. The solubility of tolbutamide increased as a function of cyclodextrin concentration, showing Bs and AL type diagrams for β-cyclodextrin and hydroxypropyl-β-cyclodextrin, respectively. The dissolution rate of tolbutamide/cyclodextrin complexes were investigated and compared with those of the physical mixtures and pure drug. The dissolution rate of tolbutamide from the inclusion complexes was much more rapid than tolbutamide alone.

Physical properties of chitosan pellets produced by extrusion-spheronisation: influence of formulation variables

Pellets comprising chitosan, cellulose microcrystalline, povidone, filler excipient and diclofenac sodium as model drug were prepared by extrusion-spheronisation. The effects of chitosan load (zero, 0%, low, 4% and high, 16% levels), type of filler (lactose, tribasic calcium phosphate and beta-cyclodextrin) and composition of the binding liquid (ethanol/water mixtures 20 and 50%) on physical characteristics of pellets were evaluated. A three-factor factorial design was employed in the study. Analysis of variance (ANOVA) indicated that single factors had significant effect on the physical characteristics of the pellets. The type of filler followed by polymer load markedly affected the density. The type of binding liquid had negligible effect on the shape and surface roughness of the pellets. Increase in the chitosan load resulted in pellets of lower porosity values. This could be attributed to the binding capacity of chitosan and povidone leading to more compacted structures. Chitosan load and type of filler had significant influence on the surface roughness. The surface of pellets became rougher as the chitosan load increased, however, there was no significant difference between zero and low contents of chitosan. Pellets prepared using tribasic calcium phosphate showed a smoother surface when compared with formulations including lactose or beta-cyclodextrin. Chitosan was useful to provide pellets of acceptable physical characteristics when employing an alcohol/water mixture 50% (v/v) as binding liquid for the extrusion-spheronisation process.

Oral bioavailability and hypoglycaemic activity of tolbutamide/cyclodextrin inclusion complexes

The purpose of the present study was to evaluate the enhancement of tolbutamide (TBM) oral bioavailability and hypoglycaemic activity through complexation with beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-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 microg/ml at 8.5 h (T(max)), whereas with inclusion complexes, C(max) increased about two times and appeared at ca. 4 h. AUC(0-24) 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 (CVG(max)) of TBM (34. 1%) was observed at 5.6 h (Tg(max)). CVG(max) of TBM/beta-CD and TBM/HP-beta-CD inclusion complexes were 34.1% (at 6.5 h) and 37.7% (at 5.1 h), respectively. AAC(0-24) 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.

Starch-based coatings for colon-specific delivery. Part II: physicochemical properties and in vitro drug release from high amylose maize starch films.

This work reports an investigation into free-film properties of a high amylose maize starch-based film coating that has been used in the preparation of formulations for drug delivery to the colon (WO 2008/012573 A1) and relates these properties to in vitro drug release from pellets. Maize starch/ethylcellulose free films were prepared and characterised by scanning electron microscopy (SEM), light microscopy, modulated differential scanning calorimetry (mDSC), Fourier-transform infrared (FT-IR), X-ray and % swelling in aqueous fluids with pH conditions similar to the stomach and small intestine. 5-ASA release from film-coated pellets was tested in enzyme free simulated gastric fluid and phosphate buffer pH 7.2. Selected formulations were further assessed in simulated gastric and intestinal fluids containing pepsin and pancreatin, respectively. The free films prepared were smooth and homogeneous in their appearance. The two polymers are immiscible, and neither mDSC nor FT-IR could detect interactions between them. Films made from high amylose starches were found to have a considerably lower swelling ability than high amylopectin-based films, and they suppressed drug release in the enzyme free media successfully. 5-ASA release from pellets coated with mixtures of high amylose starches (Hylon VII, Hylon V or LAPS) and Surelease in a ratio of 1 to 2 w/w was found to be minimal in simulated gastric and intestinal fluids. This suggests that these mixed films provide starch domains that are resistant to the enzymes present in the upper GI tract and thus can potentially be used in the preparation of colon-specific delivery devices. Starches with a minimum amylose content of 56% such as the starches used in this study (Hylon VII and Hylon V) are preferred, and although pure amylose can also be used this is not essential.

Role of Cellulose Ether Polymers on Ibuprofen Release from Matrix Tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE20 h), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.

Influence of Cellulose Ether Mixtures on Ibuprofen Release: MC25, HPC and HPMC K100M

The influence of cellulose ether derivatives on ibuprofen release from matrix tablets was investigated. Raman spectroscopy and differential scanning calorimetry (DSC) experiments were used, in order to examine the compatibility between the matrix components: both excipients and ibuprofen. While both the DSC and Raman results did not detect any incompatibilities, DSC revealed the existence of some drug:excipient interactions, reflected by variations in the hydration/dehydration processes. Formulations containing mixtures of polymers with both low and high viscosity grades—methylcellulose (MC25) or hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K100M), respectively—were prepared by a direct compression method (using 20, 25, and 30% of either MC25 or HPC). The tablets were evaluated for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, surface area, and volume. Parameters such as the mean dissolution time (MDT) and the dissolution efficiency (DE) were calculated in all cases. The solid formulations presently studied demonstrated a predominantly Fickian diffusion release mechanism.

Compatibility studies between ibuprofen or ketoprofen with cellulose ether polymer mixtures using thermal analysis.

ABSTRACT Differential scanning calorimetry (DSC) was used to investigate and detect incompatibilities between drugs such as: ibuprofen (IBU) or ketoprofen (KETO) with cellulose ether derivatives, which are frequently applied on controlled release dosage forms. Binary mixtures concerning methylcellulose (MC25) or hydroxypropylcellulose (HPC) with hydroxypropylmethylcellulose (HPMC) K15M or K100M in different ratios were prepared and evaluated by the appearance, shift, or disappearance of peaks and/or variations in the corresponding ΔH values. According to the DSC results, binary mixtures between those polymers were found to be compatible, but their mixture with IBU or KETO, promotes a solid–solid interaction mainly with 1:1:1 (w/w) ratio (drug-excipient). However, when the drug:excipient interactions were detected, they were not found to affect the drug bioavailability. DSC was successfully employed to evaluate the compatibility of the drugs with the selected polymers.

Effect of Polymer Hydration on the Kinetic Release of Drugs: A Study of Ibuprofen and Ketoprofen in HPMC Matrices

Abstract Samples of drug/hydroxypropylmethylcellulose (HPMC) mixtures and matrices (drug/HPMC mixtures plus excipients) were allowed to equilibrate in closed chambers with defined relative humidities (RHs). Their water uptake and drug release were evaluated by differential scanning calorimetry/thermogravimetric analysis and dissolution studies, respectively. Analysis of the thermal behaviors of the drug/HPMC mixtures and of the polymer alone, as functions of RH, leads to the conclusion that most of the hydration water is retained by the polymer, and points to the occurrence of different types of hydration water, from the strongly polymer-bound water molecules at RH values up to 81%, to the almost “free water” for RH values close to 100%. In addition, application of the Korsmeyer model to the dissolution results leads to the conclusion that the rate determining dissolution processes are predominantly of the fickian type.

Advance in Methods Studying the Pharmacokinetics of Polyphenols

Significant advances have been achieved during the past decade concerning the metabolism of polyphenol compounds in vitro, but scarce data has been presented about what really happens in vivo. Many studies on polyphenols to date have focused on the bioactivity of one specific molecule in aglycone form, often at supraphysiological doses, whereas foods contain complex, often poorly characterized mixtures with multiple additive or interfering activities. Whereas most studies up to the middle-late 1990s measured total aglycones in plasma and urine, after chemical or enzymatic deconjugation, or both, several recent works now report the polyphenol conjugate composition of plasma, urine, feces and/or tissues, after the administration of pure polyphenols or polyphenol-rich matrices. HPLC methods with electrochemical, mass spectrometric and fluorescence detection have adequate sensitivity. LC/UV-Vis methods have also been widely reported, but they are much less sensitive. Compared with electro-chemical and fluorescence detection, MS can quantify analytes without chromatographic separation, which leads to high throughput, presenting itself as the best choice to date. Regarding the experimental model to monitor the bioavailability of phenolic compounds, most published studies are based on human and animal models, with the majority using rodents, primates and recently the nematode Caenorhabditis elegans. This review focuses on the fundamentals of pharmacokinetic methods from the last 15 years and how the results are evaluated and validated. The types of analytical methods, animal models and biological matrices were used to better elucidate pharmacokinetics of polyphenols.

Biopolymers and pilocarpine interaction study for use in drug delivery systems (DDS)

This work aimed at the investigation of pilocarpine’s interaction in the association of cashew gum (CG) and chitosan (CH) biopolymers because of mucoadhesive and prolonged release properties of this polymeric system. To elucidate this issue, characterization techniques, such as DSC, TG, XRD, IR, were applied besides DFT B3LYP/6-31++G(d,p) computational calculations. According to this approach, CG interacts with pilocarpine having a protective thermal effect on the drug and CH can reduce its thermal stability. These interactions occur, preferably, between a carbonyl group from pilocarpine and hydroxyl groups from biopolymers in which hydrogen bonds are involved. Thus, this work was able to identify interactions between the drug and the biopolymers and how, in a molecular approach, they occur. These results allow for the full understanding of the influence of each biopolymer for future pilocarpine-release systems.