M.D. Veiga

Elaboration and thermal study of interactions between cinnarizine and gelucire® 5310 physical mixtures and solid dispersions

Abstract This work involves the study of elaboration and thermal characterization of Gelucire® 53 10 -cinnarizine (10, 20, 30, 40 and 50%, w/w cinnarizine) binary systems (solid dispersions and physical mixtures). The analytical thermal techniques employed, differential scanning calorimetry (DSC) and hot stage microscopy (HSM) have demonstrated the ability of melted Gelucire® 53 10 to dissolve the crystals of cinnarizine. The high solubilizing effect of this vehicle, in comparison with other carriers, may be explained on the basis of its surfactant properties. Only at low drug percentages, can the total dissolution of cinnarizine present in the system be achieved.

Preparation, characterization and dissolution of ciprofloxacin/PEG 6000 binary systems

Abstract Thermomicroscopy and DSC were employed to study ciprofloxacin/PEG 6000 binary systems in the form of solid dispersions and physical mixtures. The dissolution processes of ciprofloxacin from the binary systems and pure ciprofloxacin were also studied.

Influence of surfactants (present in the dissolution media) on the release behaviour of tolbutamide from its inclusion complex with β-cyclodextrin

The possible competitive displacement of a drug from its cyclodextrin-based inclusion complex by a third substance was investigated by studying the dissolution behaviour of tolbutamide-beta-cyclodextrin inclusion complex in demineralised water and in aqueous solution of different surfactants. Physical mixtures and kneaded systems were prepared in 1:1 and 1:2 drug-beta-cyclodextrin mol/mol ratios and they were characterised by hot-stage microscopy, differential scanning calorimetry, and X-ray powder diffractometry. The release behaviour of tolbutamide from its inclusion complex was studied by studying the dissolution of the binary systems in water and in aqueous solutions of three surfactants: polysorbate 20, poloxyl 23-lauryl ether, and sodium lauryl sulphate. When demineralised water was used as the dissolution media, the fastest dissolution of tolbutamide was obtained from 1:2 kneaded system followed by 1:1 kneaded system. The presence of poloxyl 23-lauryl ether and sodium lauryl sulphate in the media caused a decrement in the rate and extent of dissolution of the drug from both kneaded systems in comparison with that obtained from the same systems in water. However, the release of tolbutamide from the kneaded systems remains unaffected when polysorbate 20 was present in the dissolution media. Results of this study suggest that the simultaneous presence of beta-cyclodextrin and surfactants of proper molecular structure in a pharmaceutical formulation can give rise to an unexpected dissolution of the drug.

Solubility study of tolbutamide in monocomponent and dicomponent solutions of water

Abstract Solubility of tolbutamide was studied in different monocomponent (aqueous solutions of surfactant or β-cyclodextrin) and dicomponent solutions (aqueous solutions of surfactant with β-cyclodextrin). Surfactants used were Tween 20 (Polysorbate 20), Brij 35 (Poloxyl 23 lauryl ether) and sodium lauryl sulphate. In dicomponent solutions, surfactant/β-cyclodextrin ratios were 1:1, 1:2, 1:3 mol/mol. Results of drug solubility from demineralised water and monocomponent solutions containing different surfactants in various concentrations were almost the same, even though most of the used concentrations were above the critical micelle concentrations of some of the surface active agents. Although tolbutamide/β-cyclodextrin inclusion compound was formed in the monocomponent solutions of β-cyclodextrin, however, the formation of an inclusion compound was impeded in the Brij 35/β-cyclodextrin and sodium lauryl sulphate/β-cyclodextrin dicomponent solutions. Data indicate that surfactants compete with drug molecules to form inclusion compounds with β-cyclodextrin and eventually modify the drug solubility. Results also demonstrate that the resultant competitive binding depends on the chemistry of surface active agents.

Thermal behaviour of drugs from binary and ternary systems

Abstract Thermomicroscopy and differential scanning calorimetry were employed to characterize oxodipin and griseofulvin from binary and ternary systems with PEG 6000 and Tween 20. The interaction resulting between drug and PEG 6000 during heating allowed the preparation of solid dispersions. An oxodipin/PEG 6000 10:90 (w/w) solid dispersion was formed exclusively by mixed crystals of PEG 6000 and drug which were detected by thermomicroscopy. The rest of the solid dispersions prepared (with or without surfactant agent) were formed by mixed crystals and particles of pure drug. The presence of Tween 20 does not appear to affect the thermal behaviour between drugs and PEG 6000.

Influence of Chitosan Swelling Behaviour on Controlled Release of Tenofovir from Mucoadhesive Vaginal Systems for Prevention of Sexual Transmission of HIV

The main challenges facing efforts to prevent the transmission of human immunodeficiency virus (HIV) are the lack of access to sexual education services and sexual violence against young women and girls. Vaginal formulations for the prevention of sexually transmitted infections are currently gaining importance in drug development. Vaginal mucoadhesive tablets can be developed by including natural polymers that have good binding capacity with mucosal tissues, such as chitosan or guar gum, semisynthetic polymers such as hydroxypropylmethyl cellulose, or synthetic polymers such as Eudragit® RS. This paper assesses the potential of chitosan for the development of sustained-release vaginal tablets of Tenofovir and compares it with different polymers. The parameters assessed were the permanence time of the bioadhesion—determined ex vivo using bovine vaginal mucosa as substrate—the drug release profiles from the formulation to the medium (simulated vaginal fluid), and swelling profiles in the same medium. Chitosan can be said to allow the manufacture of tablets that remain adhered to the vaginal mucosa and release the drug in a sustained way, with low toxicity and moderate swelling that ensures the comfort of the patient and may be useful for the prevention of sexual transmission of HIV.

Pectin/anhydrous dibasic calcium phosphate matrix tablets for in vitro controlled release of water-soluble drug.

Different pectin/anhydrous dibasic calcium phosphate (ADCP) matrix tablets have been developed in order to obtain controlled release of a water-soluble drug (theophylline). Swelling, buoyancy and dissolution studies have been carried out in different aqueous media (demineralized water, progressive pH medium, simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid), to characterize the matrix tablets. When the pectin/ADCP ratio was ≥0.26 (P1, P2, P3 and P4 tablets) a continuous swelling and low theophylline dissolution rate from the matrices were observed. So, pectin gel forming feature predominated over the ADCP properties, yielding pH-independent drug release behavior from these matrices. On the contrary, pectin/ADCP ratios ≤0.11 (P5 and P6 tablets) allowed to achieve drug dissolution pH dependent. Consequently, the suitable selection of the pectin/ADCP ratio will allow to tailor matrix tablets for controlled release of water-soluble drugs in a specific manner in the gastrointestinal tract.

In vitro Evaluation of Acyclovir/Chitosan Floating Systems

Chitosan (CS) floating lyophilized formulations (L) for gastric drug delivery of acyclovir (ACV) have been developed. The freeze-dried formulations were obtained from acidic aqueous suspensions prepared with different ACV/CS ratios. No changes in ACV crystallinity were observed during X-ray diffraction powder studies as a consequence of the manufacturing process. Considering that fed and fasted states modified the intragastric pH, swelling and in vitro dissolution studies were carried out in different acidic media (0.1 M HCl and progressive pH medium) in order to understand the influence of these physiological states on ACV/CS formulations. Swelling behavior of the floating lyophilized formulations was dependent on CS and ACV proportions within L and on medium nature due to pH dependent CS solubility. Furthermore, no interactions between ACV and CS were detected in solid state according to the X-ray studies. In vitro dissolution of ACV from L was influenced by the swelling behavior. However, it is feasible to optimize the ACV/CS ratios to achieve a desired formulation that releases the total quantity of ACV at a specific time. Moreover, floatability was assessed by buoyancy tests. The results demonstrated that the freeze-drying process achieved effective floating systems capable of remaining within the stomach while the total amount of ACV is released from L.

Dissolution study of spiramycin : influence of agitation intensity and addition of several substances to the dissolution medium

Abstract The dissolution process of spiramycin, a low dissolution rate drug, was studied testing the drug alone and in physical mixtures, using different additives in the medium such as hydrophilic carriers (PEG 6000 and PVP) and surface-active agents (Tween 20 and sodium lauryl sulfate), at two stirring rates (100 and 30 rpm). In most cases, a significant improvement in the dissolution rate of spiramycin was observed, the largest enhancements corresponding to those assays of physical mixtures containing sodium lauryl sulfate, in this case the dissolution rate being practically independent of the experimental stirring rate. From these assays, it was seen that sodium lauryl sulfate has considerable wetting power, even greater than that of Tween 20 (whose wetting capacity depends strongly on medium concentration and stirring rate) for spiramycin. It was also demonstrated that hydrophilic carriers may improve dissolution rate only in physical mixtures, since they act as disaggregants, diminishing electrostatic forces that exist among drug particles.

Freeze-dried bioadhesive vaginal bigels for controlled release of Tenofovir

Abstract Nowadays, million women live with the human immunodeficiency virus (HIV) worldwide and many of them are dying per year, particularly in Sub‐Saharan Africa. The development of systems that can be accessed by this population group to prevent the sexual transmission of the virus is therefore necessary. The aim of this work was the formulation of freeze‐dried bioadhesive vaginal bigels releasing Tenofovir in a controlled manner. Systems containing three different proportions of guar gum hydrogel and sesame oil were prepared, adding Span®60 or Span®60 and Tween®60 as surfactants. Drug and excipients were evaluated by cytotoxicity assays, showing no toxicity at the concentrations tested neither for the drug nor any of the excipients. Fresh formulations were characterised through texture analyses and confocal laser microcopy. The system with the lowest guar gum hydrogel/sesame oil proportion and containing Span®60 and Tween®60 (batch ST1) had the highest consistency and adhesion capacity according to texture analyses. Furthermore, a genuine bigel microstructure was observed. After freeze‐drying, swelling, bioadhesion and drug release tests were performed on the resulting systems. ST1 showed the longest bioadhesion time and the most controlled release, as well as a low swelling grade, becoming an interesting option for preventing HIV sexual transmission in women. Graphical abstract Figure. No Caption available.