A new biodegradable polythiourethane as controlled release matrix polymer.

The main aim of this paper is the synthesis and characterization of a new linear functional biodegradable polythiourethane-d,l-1,4-dithiothreitol-hexamethylene diisocyanate [PTU(DTT-HMDI)]. The SeDeM diagram has been obtained to investigate its suitability to be processed through a direct compression process. Furthermore, the ability of this polymer to act as controlled release matrix forming excipient has been studied. Four batches of matrices containing 10-40% of polymer and theophylline anhydrous as model drug have been manufactured. Release studies have been carried out using the paddle method and the polymer percolation threshold has been estimated. The principal parameters of the SeDeM Expert system, such as the parametric profile (mean radius) and the good compression index (IGC=4.59) for the polymer are very close to the values considered as adequate for direct compression even with no addition of flow agents. Furthermore, the results of the drug release studies show a high ability of the polymer to control the drug release. The excipient percolation threshold has been estimated between 20% and 30% w/w of polymer.

Collaboration between HPMC and NaCMC in order to reach the polymer critical point in theophylline hydrophilic matrices.

Percolation theory has been applied in order to study the existence of critical points as well as the possibility to find a "combined percolation threshold" for ternary hydrophilic matrices prepared with HPMC, NaCMC, and theophylline. For this purpose, different batches of ternary as well as binary hydrophilic matrices have been prepared. Critical points have been found for binary hydrophilic matrices between 21.5 and 31.3% (v/v) of HPMC and between 39 and 54% (v/v) of NaCMC, respectively. In a previous work carried out with the same polymers but a much more soluble drug (KCl), it was demonstrated the existence of a partial collaboration between the polymers in order to establish the gel layer. In this work, it has been observed for the first time the need of a minimum concentration of one of the matrix-forming polymer (between 10 and 20% v/v, approximately) for establishing an effective collaboration.

Study of the critical points of experimental HPMC-NaCMC hydrophilic matrices.

The purpose of the present work was to study the existence of critical points on the drug release and water uptake behaviour of ternary hydrophilic matrix tablets and to study the possibility of simplifying a ternary to a binary system. The ternary hydrophilic matrix tablets were prepared between 40 and 100% (w/w) of KCl, HPMC and NaCMC. Dissolution studies were carried out using the paddle method and the water uptake studies were measured using the modified Enslin apparatus and the behaviour of the kinetic parameters was studied. According to the percolation theory, both studies confirm the existence of critical points; those were related to the excipients percolation tresholds. The percolation thresholds for the binary hydrophilic matrix tablets were found between 28.7-40.7% (v/v) of HPMC and 38.6-53.9% (v/v) of NaCMC. For the ternary hydrophilic matrix tablets, the existence of a critical barrier between 54 and 61% (v/v) KCl (60-70%, w/w of KCl) was found. In the studied ternary systems HPMC and NaCMC showed that is not possible to simplify the system but they present a partial collaboration in order to establish the gel layer. The knowledge of this critical barrier will be useful in order to optimize the design of the ternary hydrophilic matrix systems.

Matrices hidrófilas. influencia del tamaño de partícula y de la solubilidad del fármaco / Hidrophilic matrix: influence of the particle size and drug solubility

Los comprimidos con matrices hidrófilas son una de las formas farmacéuticas orales más utilizadas para liberación controlada. La liberación del fármaco está basada en la transición de estado cristalino a estado elástico, que experimenta el polímero debido a la penetración de agua en la matriz siendo la disolución del fármaco, el hinchamiento y la erosión de la matriz los procesos que determinan la liberación del fármaco desde matrices hinchables, tanto a nivel macroscópico como molecular. En matrices hidrófilas, las variaciones en el tamaño de partícula tanto del principio activo como del excipiente, producen variaciones en la velocidad de liberación del fármaco causadas por la velocidad a la que se disuelve el fármaco o la eficiencia de la formación del gel. En general, la velocidad de liberación del fármaco desde matrices hidrófilas disminuye al disminuir el tamaño de partícula del excipiente. El estudio de la influencia de la solubilidad en la liberación de fármacos desde matrices hidrófilas es un tema tratado ampliamente en la literatura; en general, los fármacos solubles se liberan principalmente por difusión de las moléculas disueltas a través del gel y los poco solubles por erosión de la matriz

Hydrophilic matrix tablet are among the most popular orally administered types of controlled release systems. Drug release from swellable matrix tablets is based on the glassy-rubbery transition of the polymer which occurs as a result of water penetration into the matrix. Therefore, the gel layer is physically delimited by the erosion (swollen matrix-solvent boundary) and swelling (glassy-rubbery polymer boundary) fronts. Previous works have investigated how the employ of hydrophilic polymers of different particle size fractions affects drug release rate. As particle size of the polymer increases, the drug release rate increases. This effect can be explained assuming that particles of increasing size require increasing time for water penetration in order to swell, as a previous step before the particles bind together and form a stable gel barrier. A number of publications have reported effect of drug solubility from hydrophilic, monolithic matrices. Many authors have concluded that water-soluble drugs are released primarily by diffusion of dissolved drug molecules across the gel layer, while poorly water-soluble drugs are released predominately by erosion mechanism

Propiedades del subcitrato de bismuto coloidal (SBC) en el tratamiento de desórdenes gastrointestinales / Properties of colloidal bismuth subcitrate (CBS) in the treatment of gastrointestinal disorders

Durante dos siglos las preparaciones de bismuto han sido útiles en una variedad de desórdenes gastrointestinales. Una renovada atención sobre la terapia con bismuto surgió cuando se demostró que los compuestos de bismuto son efectivos contra la infección por Helicobacter pylori. La necesidad de su erradicación total ha potenciado el uso del subcitrato de bismuto coloidal (SBC). En este sentido, parece actuar por varios mecanismos. El presente trabajo de revisión describe la farmacología del SBC en el tratamiento de descontroles gastrointestinales. El uso prolongado de compuestos de bismuto a dosis elevadas, que se produjo en el pasado, dio lugar a la aparición de efectos adversos serios. Los estudios sobre la administración oral de SBC sugieren que, utilizado en las dosis recomendadas, ha sido efectivo y seguro. No obstante, la posible toxicidad de las preparaciones de bismuto debe tenerse presente. En el presente trabajo se muestra una descripción de absorción, distribución, eliminación y toxicidad del SBC. Años atrás no había ningún estudio sistemático sobre las relaciones de estructura-actividad del SBC. Sin embargo, recientemente se ha producido un importante progreso en esta área. Así que, otro aspecto interesante de esta revisión es que resume, discute y describe las principales propiedades físicas, químicas y estructurales de SBC

Bismuth preparations have been useful in a variety of gastrointestinal disorders for two centuries. A renewed attention in bismuth therapy arose when it was shown that bismuth preparations are effective against Helicobacter pylori infection. The need for its total eradication has resulted in the use colloidal bismuth subcitrate (CBS). In this sense, it appears to act via several mechanisms. Present review describes CBS pharmacology in the treatment of gastrointestinal disorders. The prolonged use of high dose bismuth compounds in the past has shown some serious side effects. The studies on CBS oral administration suggests that, utilized in recommended dosages, it has been effective and safe. Nevertheless, the possible toxicity of bismuth preparations should be kept in mind. A description about CBS absorption, distribution, elimination and toxicity are shown in the present review. In the past, there had been no systematic study of the structure-activity relationships of CBS. Recently, however, there has been important progress in this area. So, another interesting aspect of this review is that summarizes, discusses and describes the main physical, chemical and structural properties of CBS

Aplicaciones terapéuticas presentes y futuras del subcitrato de bismuto coloidal (SBC) / Present and future therapeutical applications of Colloidal Bismuth Subcitrate (CBS)

El descubrimiento del efecto bactericida del subcitrato de bismuto coloidal (SBC) sobre Helicobacter pylori ha fomentado la realización de estudios en los que se utiliza este fármaco, sólo o en combinación con otros, para tratar a pacientes con gastritis o úlcera péptica. La erradicación total de H. pylori es fundamental para prevenir las recidivas. En este sentido, los resultados obtenidos utilizando diferentes combinaciones farmacológicas de SBC han sido prometedores. En la primera parte del presente trabajo de revisión se describen los principales regímenes erradicadores de H. pylori utilizando SBC. Existe poca información sobre la acción del SBC en la mucosa colónica. Sin embargo, algunos autores han investigado los efectos beneficiosos de este fármaco a nivel del tracto gastrointestinal. Por consiguiente, en la parte segunda del trabajo de revisión se describen los estudios más recientes relacionados con una nueva y potencial aplicación del SBC en otras enfermedades del aparato digestivo (AU)

[Natural "dopaminotrophic" cell transplant: a new concept in antiparkinsonian therapy]. / Trasplante de células naturales "dopaminotroficas": nuevo concepto terapéutico antiparkinsoniano.

AIM AND METHOD: Parkinson s disease is caused by the degeneration of dopaminergic neurons of substantia nigra projecting to striatum. Cellular substitution represents a potentially treatment once beneficial levodopa effects wear off. A promising therapeutic approach is grafting cells or other vectors which release neuroprotective molecules that stimulate regeneration in the damaged nigrostriatal system or, in other words, that exert a dopaminotrophic action. We have tested the suitability of intrastriatal grafts of extra adrenal chromaffin cells taken from the Zuckerkandl s organ. This paraganglion contains chromaffin cells that express and release glial cell line derived neurotrophic factor (GDNF) and transforming growth factor b1 (TGF b1), both known to protect dopamine cells in vitro and in vivo. Grafts induced a functional recovery of parkinsonian rats which developed over months. The beneficial effects of grafts of the Zuckerkandl s organ were related to long survival of grafted cells, striatal reinnervation, enhancement of dopamine levels in the host striatum, and the cell delivery into the host striatum of GDNF and TGF b1. CONCLUSION: Our result should stimulate research on the clinical applicability of transplants of the Zuckerkandl s organ in Parkinson s disease

Trasplante de células naturales 'dopaminotróficas': nuevo concepto terapéutico antiparkinsoniano / Natural 'dopaminotrophic' cell transplant: a new concept in antiparkinsonian therapy

Objetivo y desarrollo. La enfermedad de Parkinson se debe a la degeneración de las neuronas dopaminérgicas de la sustancia negra que proyectan a los ganglios basales. La sustitución celular es un tratamiento potencial una vez que los efectos beneficiosos de la levodopa desaparecen. Una terapia prometedora es el trasplante de células u otros vectores, que segreguen moléculas neuroprotectoras capaces de estimular la regeneración del circuito nigroestriatal dañado o, en otras palabras, que ejerzan una acción dopaminotrófica. En mi laboratorio se ha ensayado en ratas parkinsonianas con células cromafines extraadrenales obtenidas del paraganglio de Zuckerkandl.Estas células expresan los factores neurotróficos GDNF y TGFb1, ambos protectores de neuronas dopaminérgicas tanto in vitro como in vivo. Los trasplantes indujeron en las ratas una notable mejoría funcional que evolucionó durante meses. Los efectos funcionales se asociaron a una larga supervivivencia de las células trasplantadas, reinervación estriatal, incremento de los niveles de dopamina en el estriado hospedador y liberación de los factores GDNF y TGFb1 por las células cromafines trasplantadas. Conclusión. Este resultado debería estimular el ensayo de la posible aplicación clínica del trasplante de células cromafines extraadrenales del paraganglio de Zuckerkandl en la enfermedad de Parkinson (AU)

Aim and method. Parkinson’s disease is caused by the degeneration of dopaminergic neurons of substantia nigra projecting to striatum. Cellular substitution represents a potentially treatment once beneficial levodopa effects wear off. A promising therapeutic approach is grafting cells or other vectors which release neuroprotective molecules that stimulate regeneration in the damaged nigrostriatal system or, in other words, that exert a dopaminotrophic action. We have tested the suitability of intrastriatal grafts of extra-adrenal chromaffin cells taken from the Zuckerkandl’s organ. This paraganglion contains chromaffin cells that express and release glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-b1 (TGF-b1), both known to protect dopamine cells in vitro and in vivo. Grafts induced a functional recovery of parkinsonian rats which developed over months. The beneficial effects of grafts of the Zuckerkandl’s organ were related to long survival of grafted cells, striatal reinnervation, enhancement of dopamine levels in the host striatum, and the cell delivery into the host striatum of GDNF and TGF-b1. Conclusion. Our result should stimulate research on the clinical applicability of transplants of the Zuckerkandl’s organ in Parkinson’s disease (AU)

Stability study of flutamide in solid state and in aqueous solution.

A high-performance liquid chromatography (HPLC) assay has been developed for the determination of flutamide and its degradation products. Using this method, the influence of important formulation factors on the stability of flutamide has been estimated. The stability studies have been carried out in solid state as well as in aqueous solution. The results obtained have shown a good stability for flutamide in solid state. This drug remained practically unchanged after a four-month assay in adverse temperature and humidity conditions. On the other hand, the results obtained from the stability study in solution during 12 days have shown that flutamide in aqueous solution underwent a clear degradation at mean or high temperature (22 degrees C, 37 degrees C) and acidic pH conditions (1.1). With respect to the influence of ionic strength, it has been found that the presence of sodium chloride prevents the degradation of flutamide in aqueous solution. The second-order kinetics model provides the best fit for highly degraded solutions.

Functional regeneration in a rat Parkinson's model after intrastriatal grafts of glial cell line-derived neurotrophic factor and transforming growth factor beta1-expressing extra-adrenal chromaffin cells of the Zuckerkandl's organ.

Intrabrain transplantation of chromaffin cell aggregates of the Zuckerkandl's organ, an extra-adrenal paraganglion that has never been tested for antiparkinsonian treatment, induced gradual improvement of functional deficits in parkinsonian rats. These beneficial effects were related to long survival of grafted cells, striatal reinnervation, and enhancement of dopamine levels in grafted striatum. Grafted cells were not dopaminergics, but they expressed glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta(1). These factors were detected in the host striatal tissue, indicating that chromaffin cells secreted them after grafting. Because glial cell line-derived neurotrophic factor possesses neurorestorative properties over dopaminergic neurons, and transforming growth factor-beta(1) is a cofactor that potentiates the neurotrophic actions of GDNF, functional regeneration was likely caused by the chronic trophic action of neurotrophic factors delivered by long-surviving grafted cells. This work should stimulate research on the clinical applicability of transplants of the Zuckerkandl's organ in Parkinson's disease.

Estimation of the percolation thresholds in dextromethorphan hydrobromide matrices.

Percolation theory is a multidisciplinary theory that studies chaotic systems. It has been applied in the pharmaceutical field since 1987. Knowledge of the percolation threshold -- one of the most important concepts in percolation theory -- results in a clear improvement of the solid dosage form design. The percolation threshold is the concentration showing the maximum probability to obtain, for the first time, a percolating cluster of a substance. In this work, the percolation thresholds of dextromethorphan.HBr/Eudragit RS-PM inert matrices were estimated. The drug percolation threshold was estimated as 0.3691+/-0.0541 (P=0.05) of the total porosity (ranging between 23 and 36% w/w of drug). The SEM micrographs of the matrices are consistent with the estimated percolation range. In agreement with previous reports, different percolation thresholds were found for the matrix forming excipient Eudragit RS-PM. The site percolation threshold (based on the release properties) ranged between 10 and 20% v/v of the excipient, the site-bond percolation threshold (estimated from the mechanical properties) between 29.5 and 34% v/v of the excipient and the swelling percolation threshold between 34.3 and 46.9% v/v of the excipient. These percolation ranges are in agreement with those found previously for Eudragit RS-PM matrices containing naltrexone.HCl and morphine.HCl.

Percolation thresholds in ultrasound compacted tablets.

Twenty matrix systems with different KCl content (as drug model, from 10 to 90% w/w) and Eudragit RS-PM (as inert excipient) were prepared using an ultrasound-assisted press and a traditional eccentric machine. The release behavior from both types of matrices was examined; the kinetic parameters for the release (intrinsic dissolution) and the technological properties of the final tablets (total porosity) were used to estimate the percolation threshold for the drug model and the excipient in both systems. For the systems compacted by ultrasound (US) the estimated value for the excipient percolation threshold ranges from 13.4 to 20.2% v/v (lower than that found for traditional tablets), that agrees with a continuum percolation model suggesting the presence of a continuum phase inside the tablet. This depends on a thermoplastic deformation of Eudragit RS-PM under ultrasound, that destroyed the particulate system of the excipient and transform it into a continuum medium. The percolation threshold for KCl ranged from 58.6 to 61.0% v/v for US and from 26.7 to 42.2% v/v for the traditional tablets. The higher value for ultrasound compacted tablets can be explained by the difficulty of KCl to outcome from a matrix containing insoluble phase that surrounds KCl crystals.

Preclinical study of an oral controlled release naltrexone complex in mice.

Naltrexone, a long-acting, orally effective, opioid antagonist which blocks opioid effects as well as the development of physical dependence, would appear to be a drug ideally suited to addiction treatment. An optimal dosage regimen is critical for the treatment patient compliance in ambulatory opiate detoxification programs. The ideal dosage regimen would be an oral controlled-release system of naltrexone that allowed once-a-day administration providing stable plasma levels. A naltrexone-Eudragit L complex was produced in aqueous medium from naltrexone hydrochloride solution and Eudragit L30D (30% w/v) previously diluted (6% w/v) and partially neutralized. The antagonistic activity of naltrexone-Eudragit L on morphine-induced thermal antinociception, in comparison with conventional naltrexone, was evaluated, using the mouse hot-plate model. Mice were administered 10 mg kg(-1) morphine subcutaneously, 10 min before test, and the antagonist products, either naltrexone-Eudragit L or naltrexone hydrochloride, were administered orally at 0.5, 1, 2, 4, 6, 8, 10, 12, 14 and 16h before the test. The results showed that the antagonism induced by naltrexone-Eudragit L was effective until 12 h after drug administration, while that induced by naltrexone hydrochloride disappeared 10 h after its administration. A 23.47% increase of the area under curve was obtained when naltrexone-Eudragit L was administered, compared with that induced by conventional naltrexone. The time taken to decrease the inhibition of analgesic activity to 50% was delayed by 51.80%. This complexation technique can be considered as a useful tool in the design of oral controlled-release systems capable of inducing a long-lasting effect in-vivo.

Statistical optimization of a sustained-release matrix tablet of lobenzarit disodium.

The statistical optimization of sustained-release matrix tablets of lobenzarit disodium salt (LDS) was performed using the central composite experiment design 2(3) for three independent variables: the amount of polymer (Eudragit RS-PO) AP, the total volume of granulation solvent VS, and the amount of filler (microcrystalline cellulose) CE. The t90% was selected as the response variable. The response surfaces were performed from a statistical mathematical model. The optimal formulation was obtained for the variables (AP = 15 mg, VS = 60 microliters, and CE = 0).

Design of controlled release inert matrices of naltrexone hydrochloride based on percolation concepts.

The percolation theory is a statistical theory able to study chaotic or disordered systems that has been applied in the pharmaceutical field since 1987. Through the application of this theory, the design of controlled release inert matrices has been improved. The aim of the present paper is to estimate the percolation thresholds, the most important concept of the percolation theory, which characterise the release behaviour of controlled release inert matrices of naltrexone hydrochloride. Matrix tablets were prepared using naltrexone hydrochloride as a potent narcotic antagonist and Eudragit(R) RS-PM as matrix forming material in different ratios, keeping constant the drug and excipient particle sizes. In vitro release assays were carried out exposing only one side of the tablets to the dissolution medium. The drug percolation threshold was estimated using different methods. The method of Leuenberger and Bonny gives 31.11+/-7.95% v/v as the critical porosity, which corresponds to a percolation range from 12 to 20% (w/w) of drug content. The release profiles and the release kinetics are in agreement with this result. A change in the exponent k (from 0.29 to 0.57) has been found in this region. Using scanning electron microscopy, the percolation threshold has been observed in a higher concentration range (20-35% w/w). This fact can be attributed to the low accuracy of the visual methods, mainly due to the extrapolation from 2D to 3D systems. If a percolating cluster is observed in two dimensions, the percolation threshold of the 3D system will be already clearly exceeded. The excipient percolation threshold is estimated between 25.4 and 31.1% (v/v) based on the release profiles and the analysis of the release kinetics.

Evaluation of Eudragit RS-PO and Ethocel 100 matrices for the controlled release of lobenzarit disodium.

Lobenzarit disodium is a drug for the treatment of rheumatoid arthritis. In this work, inert matrix tablets of lobenzarit disodium were prepared by direct compression using Ethocel 100 and Eudragit RS-PO as polymeric materials in different ratios. The obtained powder mixtures and tablets were evaluated from the rheological and technological points of view. The dissolution test was performed to evaluate the in vitro release kinetic of the matrices. The obtained dissolution profiles demonstrated that the matrices containing Eudragit RS-PO showed a slower release rate and therefore were more suitable for controlling the release of drug. The fit to the Higuchi model indicates that the drug release mechanism from these matrices was controlled by the diffusion step.

The role of the drug/excipient particle size ratio in the percolation model for tablets.

PURPOSE: In previous papers, a linear relationship between drug particle size and drug percolation threshold was found in inert matrix tablets. The main objectives of the present work are: to study the influence of the excipient particle size on the drug percolation threshold and to investigate if the change in the drug percolation threshold is due either to the absolute or to the relative drug particle size. METHODS: Matrix tablets have been prepared using KCl (7 different particle size fractions) as a drug model and Eudragit RS-PM (4 granulommetric fractions) as matrix forming material. In vitro release assays were carried out on the 66 lots of tablets. The drug percolation thresholds were estimated following the method of Bonny and Leuenberger. RESULTS: The particle size of the excipient has shown an opposite effect to the drug size on the drug percolation threshold. Nevertheless, the influence of drug and excipient sizes on the drug percolation threshold are of the same magnitude. CONCLUSIONS: The drug percolation threshold depends linearly on the relative drug particle size. This finding is in agreement with percolation theory and can facilitate the use of the percolation threshold as a preformulation parameter to improve the pharmaceutical dosage forms design.

Relationship between drug percolation threshold and particle size in matrix tablets.

PURPOSE: Since a previous qualitative study carried out by us showed the existence of an important influence of the particle size on the percolation thresholds and taking into account that the existing theoretical models can only provide qualitative explanation to this influence, the purpose of this work is to carry out the first quantitative study of the influence of the particle size over the drug percolation thresholds. METHODS: Matrix tablets have been elaborated using potassium chloride as drug model and Eudragit RS-PM as matrix forming material. Five different KCl particle size fractions have been employed whereas the Eudragit RS-PM particle size was kept constant. In-vitro release assays were carried out for all the elaborated lots. The drug percolation thresholds were estimated following the method proposed by Bonny and Leuenberger. RESULTS: A linear relationship has been found between the drug particle size and the corresponding drug percolation threshold. CONCLUSIONS: This finding confirms the results previously obtained in our qualitative study and has important repercussions in the design of pharmaceutical solid dosage forms. If this linear behaviour is general, the percolation threshold can soon become a useful preformulation parameter.

A rapid HPLC method for the quantification of tyrothricin, menthol, and benzocaine in pharmaceutical formulations.

A rapid, sensitive, and accurate reversed-phase HPLC method has been developed for the analysis and quantification of pharmaceutical formulations containing tyrothricin (1), an antibiotic used in antiseptic buccal compressed tablets for local application. The assay has been carried out under isocratic conditions, using a stationary phase of alumina particles coated with polybutadiene and an alkaline mobile phase (pH = 8.2). No HPLC method was reported for the analysis of 1. So, this new technique is an alternative to the slow and tedious microbiological methods. On the other hand, it allows the simultaneous quantification of 1, benzocaine (2), and menthol (3), an aromatic compound not currently analyzed by liquid chromatography.