In vitro evaluation of sustained released matrix tablets containing ibuprofen: a model poorly water-soluble drug

ABSTRACT A matrix system was developed that releases ibuprofen (IB) over a 12-hour period and the influence of the polymer type and concentration on the release rate of the drug was evaluated. Tablets containing different concentrations of Carbopol (CP), hydroxypropyl methylcellulose (HPMC), or ethyl cellulose (EC) were prepared using direct compression and the drug content, content uniformity, hardness, friability, dissolution performance, and in vitro release kinetics were examined. Formulated tablets were found to be within acceptable limits for physical and chemical parameters. The release kinetics of the Carbopol(r)971P 8% formulation showed the best linearity (r 2 =0.977) in fitting zero-order kinetics, suggesting the release rate was time independent. The drug release from tablets containing 8% CP was extended over approximately 18 hours and the release kinetics were nearly linear, suggesting that this system has the potential to maintain constant plasma drug concentrations over 12 hours, which could reduce the frequency of administration and the occurrence of adverse effects associated with repeated administration of conventional IB tablets

Radiopharmaceuticals as modern metal complexes

RADIOPHARMACEUTICALS AS MODERN METAL COMPLEXES Chelation is a chemical process in which a substance is used to bind molecules, such as metals or minerals, and hold them tightly so that they can be removed from a system, such as the body. In medicine, chelation has been scientifically proven to rid the body of excess or toxic metals: a person who has lead poisoning may be given chelation therapy in order to bind and remove excess lead from the body before it can cause damage. In the case of EDTA chelation therapy, the substance that binds and removes metals and minerals is EDTA. EDTA was first used in the 1940s for the treatment of heavy metal poisoning to remove heavy metals and minerals from the blood, such as lead, iron, copper, and calcium, and is approved by the U.S. Food and Drug Administration (FDA) for use in treating lead poisoning and toxicity from other heavy metals. Chelation therapy will remove excessive levels of 13 elements from the body -- lead, mercury, nickel, cadmium, and aluminum -- all toxic elements. It also will remove some good minerals from your body as well -- such as chromium, copper, iron, magnesium, manganese, and calcium. It is important to take mineral supplements to counteract this while on chelation therapy. The EDTA is eliminated from the body, 95 per cent via the kidneys and 5 per cent via the bile, along with the toxic metals and free ionic calcium, which it has locked on to in its transit through the circulatory system. Although it is not approved by the FDA to treat CAD (Coronary Artery Disease or angina pectoris), some physicians and alternative medicine practitioners have recommended EDTA chelation as a way to treat this disorder. Chelation with EDTA has a low occurrence of side effects: the most common one is a burning sensation experienced at the site where the EDTA is delivered into the veins. Rare side effects can include fever, hypotension (a sudden drop in blood pressure), hypocalcemia (abnormally low calcium levels in the blood), headache, nausea, vomiting, and bone marrow depression. Several theories have been suggested for this form of CAD treatment. One theory suggests that EDTA chelation might work by directly removing calcium found in fatty plaques that block the arteries, causing the plaques to break up. Another is that the process of chelation may stimulate the release of a hormone that in turn causes calcium to be removed from the plaques or causes a lowering of cholesterol levels. A third theory is that EDTA chelation therapy may work by reducing the damaging effects of oxygen ions (oxidative stress) on the walls of the blood vessels. Reducing oxidative stress could reduce inflammation in the arteries and improve blood vessel function. None of these theories has been well tested in scientific studies. There is a lack of adequate prior research to verify EDTA chelation therapy's safety and effectiveness for CAD. Ethylene-diamine-tetra-acetic acid is a chelating agent for electrically charged metal atoms, and incorporating them into its structure. It is also an antibacterial agent and is widely used as a preservative. EDTA has a particular affinity for heavy and toxic metals and was approved by the Federal Food and Drug Administration as a treatment for lead poisoning in 1959. Unexpectedly, lead-poisoning victims who also suffered symptoms of arteriosclerosis reported that chelation reduced their angina and leg pain and increased their endurance. Because of these unforeseen benefits, doctors began studying the effects of EDTA on patients with arteriosclerosis. Some chelationists believe that the therapy works because EDTA helps unclog the circulatory system by drawing calcium from plaque or that all of EDTA\u2019s various effects stem from its proven action, as a lead chelator. Others say the EDTA helps reduce the effects of free radicals\u2014highly reactive atomic structures lacking one electron that contribute to the process of aging. Chitosan is a ..

Microencapsulation of sodium diclofenac in alginate/chitosan particulate systems

The use of biodegradable polymeric carriers for the drug delivery systems has gained a wide interest, mainly for their biocompatibility and, among the microparticulate systems, microspheres show a special importance for providing local as well as temporal controlled release of the drug. Different types of polymers are encountered in the literature used to this purpose. In the case of the release of diclofenac are available: poly-3-caprolactone, poly-/vinylalcohol, poly-lactide-co-glycolide. Also natural polymers found their application in this field: albumin, alginate, carboxymethyl-cellulose, chitosan. The preparation and characterization of the samples are quite similar in most cases. The anti-inflammatory drug (as sodium salt) is dissolved in an aqueous solution containing the soluble polymer and, in the case of carboxylate-containing polymers (alginate, carboxymethyl cellulose), the formation of microspheres was obtained by the addition of Ca2+ or Al3+: the hydrophilic colloids interact with metal ions to form crosslinked insoluble complexes, that precipitate incorporating the drug. In this paper, we prepared microspheres of alginate containing sodium diclofenac and examined the different influence of Ca2+ or Al3+ ions on the microsphere morphology and the influence of different amounts of chitosan on the release of diclofenac. Among polyanionic polymers alginate has been widely studied and applied for its possibilit\ue0 to modulate the release, according to the properties of its carboxyl groups as well as its biodegradability and absence of toxicity. Also chitosan finds wide applications in pharmaceutical technology as tablet disintegrant, for the production of controlled release solid dosage forms or for improvement of drug dissolution Diclofenac is a suitable candidate for incorporation into microspheres to minimize its adverse effect after oral administration; in fact, alginate microspheres containing diclofenac start to release the drug after the pH of the environment increases above 7, by-passing the gastric environment and avoid direct contact between the drug and the gastric mucosa

ELABORATION OF ALGINATE MICROSPHERES BY EMULSIFICATION-IONOTROPIC GELATION TECHNIQUE CONTAINING BIOADHESIVE POLYMERS. A MORPHOLOGICAL STUDY OF THE SYSTEMS

Natural polymers have great advantages because they have good biocompatibility, specific degradation and the feasibility to incorporate drugs into their matrices. Amongst the natural polymers, alginate has been used by many workers as a matrix for the controlled release of drugs [1, 2]. It has an ability to cause a bioadhesion with mucosal membranes. Drug delivery in the oral mucosa has many advantages for drugs such as local anaesthetics. However, this site of the oral cavity is subjected to the influence of the salivation process, that can remove the remanent dosage form from the application site. Therefore, the addition of a bioadhesive to the bead formulation could avoid this removing effect. The most commonly used technique for carrying drugs in an alginate matrix is by extruding droplets of alginate drug solution or dispersion into a calcium chloride bath. Gelation occurs by an ionic interaction between the calcium ions and the carboxylate anion of G-G blocks as calcium ions diffuse from the external source into the droplet. An alternative to these techniques is the emulsification method, which allows the encapsulation of the drug in small beads. Bead formation through emulsion techniques has not been adequately investigated with bioadhesive polymers. An emulsion of an alginate aqueous solution in oil can be added to CaCl2 solution, and thereby leads to bead formation. However, particle size cannot be easily controlled and the beads tend to coagulate into large masses before hardening properly. In the present study, the gelation of alginate-Chitosan (CH) and alginate-Gantrez\uae solution is achieved through the emulsification of this solution with the lipophilic phase. In a first stage, a morphological study by SEM has been realized, in order to determine the presence or absence of bead aggregates, and their shape parameters

Diclofenac salts, II. Solid dispersions in PEG6000 and Gelucire 50/13.

A number of systems were prepared at five compositions (5, 10, 20, 30 and 40% w/w) of diclofenac/N-(2-hydroxyethyl) pyrrolidine salt and acidic diclofenac in PEG6000 and Gelucire 50/13, as physical mixtures and as solid dispersions. Powder X-ray diffractograms for the systems examined show shifted and normal peaks, suggesting that the drug is present inside the samples in different physical states. Differential scanning calorimetry does not offer important information, since drug solubility into the carriers increases with temperature and thermograms show only the melting point peak of the carriers. Hot-stage microscopy examination explains that, in high concentration samples, the drug is present either dissolved into the carriers, or precipitated as microcrystals, or undissolved crystals of larger size. Gelucire 50/13 allows the formation of larger crystals than PEG, using both the chemical forms of the drug. The release percentage of the drug from PEG6000/acidic diclofenac reaches 50% after few minutes in the most favourable case and appears to be dependent on the composition of the samples: the more diclofenac is present as dissolved in the pre-treated samples, the higher is the release. The optimum composition was found in the range of 5-10% w/w

Modified doxorubicin for improved encapsulation in PVA polymeric micelles

Polyvinylalcohol, partially substituted with lipophilic acyl chains, generates polymeric micelles in aqueous phase, containing a hydrophobic core able to encapsulate lipophilic drugs. Two types of polymers were obtained by conjugation of polyvinylalcohol with oleoyl or linoleoyl chains as pendant groups. The polymers, at a substitution degree of approximately 1%, are soluble in water and form polymeric micelles whose size increases with polymer concentration. Doxorubicin was hydrophobized, by linking an oleoyl chain via amide bond, to make the drug more similar to the substituted polymers and promote its encapsulation into the inner core of the micelles. The properties of the drug-polymer systems were evaluated in solution by dynamic light scattering technique and correlated to the physicochemical characteristics of the drug and the substituted polymers. Solubilization tests revealed that the similarity of the chain, in both the polymer and the drug, promotes better drug encapsulation in the oleoyl than linoleoyl derivative. The drug-polymer systems are stable in phosphate buffer saline (pH 7.4) at 37 degrees C, and the release of the drug is activated by the presence of the proteolytic enzyme pronase-E. The enzyme activated drug release and the size of the polymeric micelles, compatible with the pore dimensions of the tumor vessels, make these systems interesting for targeting lipophilic drugs to solid tumors, where the proteolytic enzyme concentration strongly raises with respect to the other body compartments

DPPC vesicles containing minoxidil II: application of experimental and Taguchi design to improve formulations.

none5Purpose: The aim of this study was to optimize the minoxidil (Mx) liposome / ethosome formulations obtained by mechanical dispersion method. The (statistical) design of experiments (DOE) is an efficient procedure for planning experiments so that the data obtained can be analized to yield valid and objective conclusions. Taguchi method uses the signal-to-noise (SN) ratio, which is directly transformed from the quadratic quality loss function, as a measure to determine the robustness of a process. Methods: The effects of membrane composition, liposome size, amount of drug and number of vortexing cycles on the efficacy entrapment were studied in a 25 complete factorial design, made up of 32 runs. Based on the results from the factorial design, a new design was applied to find the optimum condition and to analyse how sensitive the reponse were to variations in the settings of the experimental variables. The SN ratio (h) was used to estimate the quality variation. The variability characteristic is inversely proportional to the SN ratio, so the larger the h is, the more robust is the system. Results: Cholesterol, ethanol and the amount of drug exerted statistical significance, while number of vortexing cycles and time did not. The optimization study carried out leaded to a ethosomal system with a high content in cholesterol. Conclusion: Experimental and Taguchi designs are two valid strategies to improve formulations of liposomes and ethosomes by optimizing the composition of the vesicles and reaction conditions. Cholesterol and ethanol constitute the most importants factors that provide high stability, flux properties and entrapment efficacy of Mx.noneJ.M. López-Pinto; J. Palma; M.L. González-Rodríguez; A. Fini; A.M. RabascoJ.M. López-Pinto; J. Palma; M.L. González-Rodríguez; A. Fini; A.M. Rabasc

PPC vesicles containing minoxidil I: characterization and in vitro permeation studies through rat skin

Purpose: Characterization of liposomes and ethosomes containing hidrophobic minoxidil (Mx) for topical administration was carried out in order to investigate the effect of preparation method and composition variables in flux properties of minoxidil through rat skin and its targeting to pilosebaceous structures. Methods: MLV liposomes and ethosomes were prepared by mechanical dispersion or Bangham method. Characterization was carried out attending to size, as a measure of stability, entrapment efficacy, morphology and lamellarity of the vesicles. Permeation studies through rat skin were conducted by means of Franz diffusion cells for all the batches investigated. In order to analize the preferential pathway of Mx across the stratum corneum toward the pilosebaceus unity, a fluorescent probe (b-carotene, bC) was used as a model drug for Confocal Laser Scanning Microscopy (CLSM) assays. Results: Mean size, entrapment efficacy, outer morphology and lamellarity were strongly influenced by the relative amount of cholesterol in the composition of the vesicles and by the presence or absence of ethanol in the medium. Flux properties of minoxidil from all systems depended as well on the cholesterol amount and the presence of ethanol in the formulation. In all cases, ethosomes exhibit better values of flux through rat skin than liposomes. All systems investigated by CLSM were compared with regard to the penetration depth of the fluorescent probe into the stratum corneum and the relative intensity of fluorescence at the pilosebaceous level. Ethosome formulation with 40 % of cholesterol (total lipid weight) showed the highest values for flux of Mx and the best targeting ability. Conclusions: DPPC vesicles were effective in delivering Mx through stratum corneum of rat skin, showing a strongly increase with regard to the drug as such. Ethosomes demonstrated to be the best formulation assayed in the targeting of the drug to the pilosebaceous structures

A new application of confocal scanning microscopy to characterize liposomes lamellarity.

none5Purpose: Lamellarity of liposomes is an important parameter that may influence the entrapment efficacy of vesicles. In order to characterize the number of lamellas of a minoxidil (Mx) liposome system, a new application of Confocal Laser Scanning Microscopy (CLSM) was developped. Methods: Different minoxidil liposomes systems were prepared by mechanical dispersion. MLV (Multilamellar vesicles) dipalmitoylphosphatidylcholine - cholesterol (DPPC – CHOL) liposomes containing Mx or fluorescent probe b-carotene (bC) were obtained. All systems investigated were characterize with regard to its entrapment efficacy, by dynamic dialysis and assayed by HPLC (Mx) or spectrofotometrically (bC). Lamellarity was analized by means of a Confocal Laser Scanning Microscope using both, fluorescence and transmitted light channels. Results: Dynamic dialysis assays revealed high entrapment efficacies both for liposomes containing Mx or bC when a certain amount of cholesterol is present in the formulation. It existed a good correlation between entrapment efficacies of Mx or bC, as not significant differences were observed for both kinds of systems. Lamellarity studies of the vesicles showed a major distribution of multilamellar vesicles for all systems studied, with a number of concentric bilayers ranged between 3 and 6. Sonicated vesicles showed a clear tendency to diminish their lamellarity, finding out a representative number of unilamellar vesicles in the formulation. Conclusion: A new technique is presented for characterization of liposomes lamellarity. CLSM constitutes a new procedure that allows to visualize number and morphology of lamellas in liposomes. CLSM provide a great imaging quality of the formulation in its aqueous medium. Non sonicated liposomes showed a multillamelar distribution, while sonication of MLV introduce a number of unilamellar vesicles in the formulation.noneJ.M. López-Pinto; J. Palma; M.L. González-Rodríguez; A. Fini; A.M. RabascoJ.M. López-Pinto; J. Palma; M.L. González-Rodríguez; A. Fini; A.M. Rabasc

DPPC vesicles containing minoxidil II: application of experimental and Taguchi design to improve formulations

Purpose: The aim of this study was to optimize the minoxidil (Mx) liposome / ethosome formulations obtained by mechanical dispersion method. The (statistical) design of experiments (DOE) is an efficient procedure for planning experiments so that the data obtained can be analized to yield valid and objective conclusions. Taguchi method uses the signal-to-noise (SN) ratio, which is directly transformed from the quadratic quality loss function, as a measure to determine the robustness of a process. Methods: The effects of membrane composition, liposome size, amount of drug and number of vortexing cycles on the efficacy entrapment were studied in a 25 complete factorial design, made up of 32 runs. Based on the results from the factorial design, a new design was applied to find the optimum condition and to analyse how sensitive the reponse were to variations in the settings of the experimental variables. The SN ratio (h) was used to estimate the quality variation. The variability characteristic is inversely proportional to the SN ratio, so the larger the h is, the more robust is the system. Results: Cholesterol, ethanol and the amount of drug exerted statistical significance, while number of vortexing cycles and time did not. The optimization study carried out leaded to a ethosomal system with a high content in cholesterol. Conclusion: Experimental and Taguchi designs are two valid strategies to improve formulations of liposomes and ethosomes by optimizing the composition of the vesicles and reaction conditions. Cholesterol and ethanol constitute the most importants factors that provide high stability, flux properties and entrapment efficacy of Mx