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Paola Mura

Publications and source records attributed to Paola Mura.

At least 19 recordsLinked to original sources
PubMed2006

Evaluation of supercritical fluid technology as preparative technique of benzocaine-cyclodextrin complexes--comparison with conventional methods.

The objective of this study was to investigate the effect of the preparation method on the physico-chemical properties of complexes prepared between beta-cyclodextrin (beta-Cyd) and benzocaine (BZC). In particular, the effectiveness of a new technique based on supercritical carbon dioxide (SC CO(2)) for preparing solid drug-cyclodextrin complexes was investigated and compared to other more conventional methods such as kneading (KN), co-evaporation (COE), co-grinding (GR) and sealed-heating (S.H.). Effects of temperature, pressure and exposure time on the properties of complexes prepared by SC CO(2) technology were also studied. The different systems were characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (PXRD) and dissolution test according to the dispersed amount method. The co-grinding (GR) method resulted in amorphous products while other methods led to crystalline or partially amorphous products depending on both the method and its experimental conditions. SC CO(2) method revealed to be an effective technique for preparing solid systems between beta-cyclodextrin and benzocaine, avoiding the use of organic solvents (and problems of their complete removal) and allowing an easy scale-up of the process. As for the influence of the experimental conditions in promoting the solid-state drug-carrier interaction when using the SC CO(2) method, temperature seemed to play the major role, whereas pressure and exposure times had more limited effects. Dissolution tests confirmed a limited but favourable effect in increasing the exposure time, while indicated a possible interaction effect between temperature and pressure in influencing the dissolution performance of the final product. The best product obtained by the SC CO(2) method showed dissolution properties similar to those of the co-ground product and only slightly lower than the system obtained by sealed-heating, which was the most effective technique.

Anesthetics, Local↗
PubMed2006

A new drug nanocarrier consisting of chitosan and hydoxypropylcyclodextrin.

The objective of the present work was to develop a new drug nanocarrier consisting of nanoparticles made of chitosan and cyclodextrins. The rationale behind the design of this new nanosystem was to simultaneously implement the cyclodextrin drug complexation power and the inherent properties of chitosan nanoparticles, in a unique delivery system. The complexation with the cyclodextrin permits the solubilization as well as the protection for sensitive drugs, whereas the entrapment in the chitosan network is expected to facilitate their absorption. Chitosan nanoparticles including hydroxypropylcyclodextrins could be prepared by the ionic crosslinking of chitosan with sodium tripolyphosphate in the presence of cyclodextrins. Two hydrophobic drugs, triclosan and furosemide, were selected as models for complexation with the cyclodextrin and further entrapment in the chitosan nanocarrier. The resulting nanosystems were thoroughly characterized for their size and zeta potential and also for their ability to associate and deliver the complexed drugs. The results showed that the size of the nanoparticles was slightly affected by the incorporation of cyclodextrins, whereas the zeta potential did not suffer a significant modification. Moreover, the complexation of the drugs with the cyclodextrin facilitated their entrapment into the nanoparticles, increasing up to 4 and 10 times (for triclosan and furosemide, respectively) the final drug loading of the nanoparticles. These results led to the conclusion that the drug-cyclodextrin complex was efficiently retained in the nanoparticulate structure. Finally, the in vitro release profile observed for these nanoparticles was characterized by an initial fast release followed by a delayed release phase. In conclusion, this new nanosystem offers an interesting potential for the transmucosal delivery of hydrophobic compounds.

Chitosan↗
PubMed2006

Effect of preparation technique on the properties of liposomes encapsulating ketoprofen-cyclodextrin complexes aimed for transdermal delivery.

The combined approach of cyclodextrin complexation and entrapment in liposomes was investigated in order to develop an effective topical formulation of ketoprofen. Equimolar complex of drug and hydroxypropyl-beta-cyclodextrin (HPbetaCyd) was added at different concentrations to the aqueous phase of liposomes consisting of phosphatidylcholine and cholesterol (60%/40%, w/w). Liposomes were prepared with different techniques, such as thin layer evaporation, freezing and thawing, extrusion through microporous membrane, and reverse phase evaporation method, obtaining, respectively, multi-lamellar vesicles (MLV), frozen and thawed MLV (FATMLV), small uni-lamellar vesicles (SUV) and large uni-lamellar vesicles (LUV). Size and morphology of the different types of liposomes were investigated by light scattering analysis, transmission electron microscopy, and confocal laser scanning microscopy, whereas drug entrapment efficiency was determined by dialysis experiments. Cyclodextrin complexation improved drug solubilization and allowed a strong improvement of its entrapment into the aqueous liposomal phase. Liposome preparation method and operating conditions clearly affected both liposome size and drug loading capacity. Encapsulation efficiency increased with increasing the complex concentration up to 10 mM, and was in the order MLV>LUV>SUV. An opposite behaviour was observed for FATMLV, probably due to the freezing phase required by such a preparation method, which reduced the complex solubility. Moreover, it was not possible to use higher complex concentrations, due to the destabilizing effect of cyclodextrins toward the liposomal membrane. Permeability studies of drug-HPbetaCyd complexes, directly in solution or incorporated in liposomes, performed across artificial membranes simulating the skin behaviour, highlighted, as expected, a prolonged release effect of liposomal formulations. Furthermore, the drug permeation rate depended on the vesicle characteristics and varied in the order: SUV>MLV=FATMLV>LUV. Therefore, the most suitable liposome preparation method can be suitably selected on the basis of drug encapsulation efficiency and/or desired drug release rate.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2006

Mixture design in the optimization of a microemulsion system for the electrokinetic chromatographic determination of ketorolac and its impurities: method development and validation.

Microemulsion EKC (MEEKC) was used for the determination of ketorolac and its three impurities. The microemulsion system was optimized, for the first time in the literature, using a multivariate strategy involving a mixture design. A 13-run experimental plan covering an experimental domain defined by the components aqueous phase (10 mM borate buffer pH 9.2), oil phase (n-heptane) and surfactant/cosurfactant (SDS/n-butanol) was carried out. Good results were obtained with all microemulsions tested considering as responses analysis time and resolution, and according to the desirability function the best microemulsion system was constituted by 90.0% 10 mM borate buffer, 2.0% n-heptane, 8.0% of SDS/n-butanol in 1:2 ratio. Finally, with the aim of reducing analysis time, a response surface study was carried out in the experimental domain defined by the process variables temperature and voltage and the best values were 17 degrees C and -17 kV, respectively. Applying the optimised conditions, a complete resolution among the analytes was obtained in about 3 min using the short-end injection method. The method was validated for both drug substances and drug product and was applied to the quality control of ketorolac in coated tablets. A comparison of MEEKC, MEKC and CEC for assaying ketorolac and its related substances has been made.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Development and evaluation of an in vitro method for prediction of human drug absorption II. Demonstration of the method suitability.

The aim of the present work was to assess the actual suitability and general applicability of a new in vitro permeation method based on an appositely developed artificial membrane to evaluate and predict drug absorption potential. The proposed method was employed to evaluate the apparent permeability of a set of 21 structurally diverse drugs having very different solubility and permeability properties, covering the whole range of fraction absorbed in humans (F(a) from 13 to 100%); 13 of the drugs in this study were part of the list suggested by FDA for validation of in vitro permeation methods. An excellent linear correlation (R(2)=0.957) was obtained between artificial membrane apparent permeability and human absorption data in the whole range of F(a) values examined (including all the drugs belonging to the above FDA list), indicating the good predictive ability of the proposed method not only for highly absorbed hydrophobic compounds but also, differently from other in vitro permeation methods, for poorly or middling permeable drugs. The predictive ability of the new method was greater than those obtained for the same set of drugs with PAMPA and Caco-2 permeability literature data, probably due to the poor sensitivity of these methods towards hydrophilic drugs. The better performance of our artificial membrane was attributed to the hydrophilic nature of the support that, differently from the commonly used hydrophobic supports, offers less resistance to permeation of hydrophilic compounds. A comparison of permeation data of theophylline, ketoprofen, aciclovir and furosemide (selected, respectively, as models of I-IV BCS classes) obtained using a Caco-2 cell based dynamic method and the developed artificial membrane and the corresponding F(a) values in humans further confirmed the suitability of the proposed permeation method as predictor of the oral absorption of passively absorbed drugs.

Acyclovir↗
PubMed2005

Development and evaluation of an in vitro method for prediction of human drug absorption I. Assessment of artificial membrane composition.

A study was undertaken aimed at developing a dynamic in vitro method based on the use of artificial membranes for screening and prediction of the absorption properties of drugs. The development of a suitable artificial membrane simulating the behaviour of the natural gastrointestinal one is the critical step for the fulfillment of this research and it has been the aim of the present work. A series of filters of different chemical nature and different characteristics (pore size, percent of porosity, thickness) were evaluated and compared in order to select the most suitable one to use as support for the artificial lipid membrane preparation. Permeation experiments were performed by using naproxen as reference model drug. The target was to achieve a naproxen apparent permeability (P(app)) value close to that previously obtained using a Caco-2 cell dynamic methodology (4.88 x 10(-5)cms(-1)), which related well to the fraction of dose absorbed in vivo in human. Filters of cellulose nitrate-acetate mixture with a porosity of 70% and 0.025 microm pore size were selected on the basis of the highest reproducibility of results and suitable drug P(app) value obtained. Mixture design experiments were then carried out in order to optimize the composition of the lipid mixture to use for porous support impregnation to obtain the desired P(app) value. Sixteen different lipid mixtures were prepared according to mixture experimental plan and evaluated by diffusion experiments. The contour plot obtained was used to select an optimum lipidic mixture (cholesterol 2.10%; Lipoid((R)) E 80 1.70%; n-octanol 96.2%) for the cellulose nitrate-acetate membrane impregnation. The experimental response obtained from diffusion experiments performed by utilising the optimised lipidic impregnation mixture, was 4.88 x 10(-5)cms(-1), matching exactly the prefixed target.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Study of formulation variables influencing the drug release rate from matrix tablets by experimental design.

Experimental design was utilized to simultaneously investigate the effect of varying the type of diluent (insoluble Calcium phosphate or water-soluble arabic gum) and the diluent/matrix ratio on the drug release behaviour from both lipophilic (glyceryl behenate, Compritol) or hydrophilic (hydroxypropylmethylcellulose) matrix tablets. Ketoprofen, theophylline and sodium sulphadiazine were selected as model drugs on the basis of their respectively very low, medium and high water-solubility, in order to evaluate the influence of this parameter as well. The selected response variables were the dissolution efficiency (i.e. the area under the dissolution curve) after one and six hours and the time necessary to dissolve 10% drug. Tablets obtained by direct compression of drug-diluent-matrix ternary mixtures prepared according to the experimental plan provided for by an asymmetric screening matrix, were tested for drug release properties using a USP paddle apparatus. Graphic analysis of the effects allowed identification, for each examined drug, of the formulation factors active on the selected responses and determination of the proper level of the variables to be selected for the response improvement. The different results obtained with the three examined drugs pointed out the role of the drug solubility in determining the influence of formulation parameters on drug release rate from matrix tablets.

Calcium Phosphates↗
PubMed2005

Preparation and characterisation of liposomes encapsulating ketoprofen-cyclodextrin complexes for transdermal drug delivery.

Multilamellar vesicle (MLV) liposomes containing ketoprofen-cyclodextrin complexes intended for drug topical delivery were prepared, with the aim of simultaneously exploiting the favourable properties of both carriers. Drug complexes with beta-cyclodextrin (betaCyd) and hydroxypropyl-betaCyd (HPbetaCyd), prepared by coevaporation and sealed-heating methods, were characterised by differential scanning calorimetry, hot stage microscopy, scanning electron microscopy and tested for dissolution properties. The coevaporated system with HPbetaCyd was the most effective, enabling an about 11-fold increase in drug dissolution. Drug and drug-Cyd systems were incorporated in MLV liposomes prepared by the thin layer evaporation technique. All liposomal formulations were characterised for encapsulation efficiency, particle size and morphology, using dialysis, light scattering and transmission electron microscopy techniques, respectively. MLV formation was negatively influenced by the presence of Cyd; nevertheless, it was possible to prepare stable MLVs containing ketoprofen-Cyd complexes. The presence of the Cyd complex affected MLV dimensions but not their lamellar structure. The complex with HPbetaCyd, in virtue of its greater stability than the betaCyd one, allowed higher percentages of encapsulation and gave rise to more stable MLV systems. Permeability studies of drug and drug-Cyd complexes, as such or incorporated in liposomes, performed both across artificial membranes and rat skin, highlighted a favourable effect of Cyd on drug permeation rate, due to its solubilizing action; by contrast, unexpectedly, no skin-permeation enhancer property of liposomes has been evidenced. Confocal laser scanning microscopy studies carried out with the rhodamine-Cyd complex as fluorescent marker, confirmed such results, showing that the label permeated deeper across rat skin layers when it was in solution than when entrapped in liposomes.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2005

Solid-state characterization and dissolution properties of naproxen-arginine-hydroxypropyl-beta-cyclodextrin ternary system.

The effect of ternary complexation of naproxen, a poorly water soluble anti-inflammatory drug, with hydroxypropyl-beta-cyclodextrin and the basic aminoacid L-arginine on the drug dissolution properties has been investigated. Equimolar binary (drug-cyclodextrin or drug-arginine) and ternary (drug-cyclodextrin-arginine) systems were prepared by blending, cogrinding, coevaporation, and characterized by differential scanning calorimetry, thermogravimetric analysis, FT-IR spectroscopy, X-ray diffractometry. The dissolution behavior of naproxen from the different products was evaluated by means of a continuous flow through method. The results of solid state studies indicated the presence of strong interactions between the components in ternary coevaporated and coground systems, which were both of totally amorphous nature. In contrast, the presence of either free drug or free arginine was detected when the third component (cyclodextrin or aminoacid) was physically mixed, respectively, to the drug-arginine binary system (as physical mixture, coevaporate, or coground product) or to the drug-cyclodextrin binary system (as physical mixture, coevaporate, or coground product). All ternary combinations were significantly (P<0.001) more effective than the corresponding binary drug-cyclodextrin and drug-arginine systems in improving the naproxen dissolution rate. The best performance in this respect was given by the ternary coevaporate, with about 15 times increase in terms of both drug relative dissolution rate and dissolution efficiency. The synergistic effect of the simultaneous use of arginine and cyclodextrin on the dissolution rate of naproxen was attributed to the combined effects of inclusion in cyclodextrin and salt formation, as well as to a specific role played by arginine in this interaction.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2005

Development of fast-dissolving tablets of flurbiprofen-cyclodextrin complexes.

The present study was aimed at developing a tablet formulation based on an effective flurbiprofen-cyclodextrin system, able to allow a rapid and complete dissolution of this practically insoluble drug. Three different cyclodextrins were evaluated: the parent beta-cyclodextrin (previously found to be the best partner for the drug among the natural cyclodextrins), and two amorphous, highly soluble beta-cyclodextrin derivatives, i.e., methyl-beta-cyclodextrin and hydroxyethyl-beta-cyclodextrin. Equimolar drug-cyclodextrin binary systems prepared according to five different techniques (physical mixing, kneading, sealed-heating, coevaporation, and colyophilization) were characterized by Differential Scanning Calorimetry, x-ray powder diffractometry, infrared spectroscopy, and optical microscopy and evaluated for solubility and dissolution rate properties. The drug solubility improvement obtained by the different binary systems varied from a minimum of 2.5 times up to a maximum of 120 times, depending on both the cyclodextrin type and the system preparation method. Selected binary systems were used for preparation of direct compression tablets with reduced drug dosage (50 mg). Chitosan and spray-dried lactose, alone or in mixture, were used as excipients. All formulations containing drug-cyclodextrin systems gave a higher drug dissolved amount than the corresponding ones with drug alone (also at a dose of 100 mg); however, the drug dissolution behavior was strongly influenced by formulation factors. For example, for the same drug-cyclodextrin product the time to dissolve 50% drug varied from less than 5 minutes to more than 60 minutes, depending on the excipient used for tableting. In particular, only tablets containing the drug kneaded with methyl-beta-cyclodextrin or colyophilized with beta-cyclodextrin and spray-dried lactose as the only excipient satisfied the requirements of the Food and Drug Administration (FDA) for rapid dissolving tablets, allowing more than 85% drug to be dissolved within 30 minutes. Finally, it can be reasonably expected that the obtained drug dissolution rate improvement will result in an increase of its bioavailability, with the possibility of reducing drug dosage and side effects.

Analgesics↗
PubMed2005

Spider Screw: skeletal anchorage system.

The stability of the anchorage unit plays a very important role in orthodontic control. Controlled orthodontic movements such as retraction and/or protraction of teeth and intrusion of overerupted teeth are very difficult to achieve without patient cooperation and without causing undesirable reciprocal movement in the anchorage unit. The article describes characteristics, surgical procedure, and clinical use of the Spider Screw as an ideal non-dental and non-cooperation based anchorage system. The Spider Screws are self-tapping, titanium mini-screws with immediate loading capability. Their utilization involves a simple biomechanical principle combined with the utilization of minimum orthodontic mechanotherapy. Ideal orthodontic forces (in the range from 50 to 250 gr) can be applied to achieve the desired orthodontic movements. Complete osteointegration is neither expected nor desired with this anchorage system. The Spider Screw anchorage system can be used to support a variety of orthodontic movements specifically in clinical situations involving incomplete dental arches and limited cooperation as in many adult orthodontic cases. The ease of surgical placement combined with the reduced dimension of the Spider Screw diameter equally permits its use in clinical situations where anchorage recovery is necessary during treatment of complete dentitions in classical orthodontic therapy.

Adult↗
PubMed2004

Influence of solvent composition on the solid phase at equilibrium with saturated solutions of quinolones in different solvent mixtures.

The dissolution profiles and solubilities of three quinolonic drugs (oxolinic, pipemidic, and nalidixic acids) in different solvent mixtures were studied. The behavior of the solid phase, during solubility experiments was in-depth investigated with the aim of detecting possible crystalline modifications, such as polymorphic transitions or solvate formations, that might modify drug stability and/or solubility properties. In order to test the influence of both the nature and polarity of the co-solvents, aqueous and non-aqueous binary mixtures have been prepared by using Lewis base (dioxane and ethyl acetate) and amphiprotic co-solvents (ethanol and water). Differential scanning calorimetry (DSC), hot stage microscopy, IR spectroscopy and X-ray powder diffraction were used in combination with solubility and dissolution studies to characterize and investigate the solid state properties of the original powders and the corresponding ones at equilibrium with the different pure solvents and solvent mixtures examined. The solid phases of nalidixic and oxolinic acids did not show any change after equilibration with the various pure solvents or binary solvent mixtures, regardless the chemical nature of the examined solvents. On the contrary, in the case of pipemidic acid, the different analytical techniques used to characterize the drug solid state enabled identification of a solvated form at equilibrium with pure dioxane and a trihydrated form in aqueous mixtures of water with both ethanol (amphiprotic) or dioxane (Lewis base) in a concentration range from 10 to 100% water.

Pharmaceutical Solutions↗
PubMed2004

Comparison of the effect of chitosan and polyvinylpyrrolidone on dissolution properties and analgesic effect of naproxen.

The solubilizing and absorption enhancer properties towards naproxen of chitosan and polyvinylpyrrolidone (PVP) have been investigated. Solid binary systems prepared at various drug-polymer ratios by mixing, cogrinding or kneading, were characterized by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy, and tested for dissolution behavior. Both carriers improved drug dissolution and their performance depended on the drug-polymer ratio and the system preparation method. Chitosan was more effective than PVP, despite the greater amorphizing power of PVP as revealed by solid state analyses. The 3/7 (w/w) drug-carrier coground systems with chitosan and PVP were the best products enabling, respectively, an improvement of 4.8 and 3.6 times of drug dissolution efficiency. In vivo experiments in mice demonstrated that administration of 45 mg/kg of drug coground with PVP or chitosan resulted, respectively, in a 25 and 60% reduction of acetic acid-induced writhings in comparison to pure drug, which, instead, was statistically ineffective as compared to the control group. Moreover, the 3/7 (w/w) drug-chitosan coground product demonstrated an antiwrithing potency 2.4 times higher than the coground with PVP. Thus, the direct-compression properties and antiulcerogenic activity, combined with the demonstrated solubilizing power and analgesic effect enhancer ability towards the drug, make chitosan particularly suitable for developing a reduced-dose fast-release solid oral dosage form of naproxen.

Acetic Acid↗
PubMed2003

Ternary systems of naproxen with hydroxypropyl-beta-cyclodextrin and aminoacids.

The purpose of the present study was to investigate the combined effect of hydroxypropyl-beta-cyclodextrin and different aminoacids (L-lysine, LYS; L-valine, VAL; L-iso-leucine, LEU; and L-arginine, ARG) on the solubility of naproxen, a poorly water-soluble anti-inflammatory drug. Aqueous solubilities of naproxen in binary and ternary systems with hydroxypropyl-beta-cyclodextrin and each aminoacid were determined. The pH was measured in all solubility studies and its role on drug solubility variation was evaluated. Arginine was the most effective aminoacid in improving drug solubility and the only one which showed a synergistic effect when used in combination with hydroxypropyl-beta-cyclodextrin. In contrast, some reduction with respect to the theoretical drug solubility (i.e. the sum of the solubilities in the presence of cyclodextrin and aminoacid separately) was observed in ternary combinations with the other aminoacids. This occurred also in the case of lysine, despite the higher solubility of its ternary system in comparison with the binary cyclodextrin complex at pH 7. Phase-solubility experiments showed that the ternary system with arginine (pH approximately 7) exhibited a stability constant 3.6 times higher and was about 5.5 times more effective in improving drug solubility than the binary complex in buffered (pH approximately 7) aqueous solutions. These results demonstrated that the high increase in the drug solubility shown by ternary systems with arginine was not simply due to a favorable pH change but to multicomponent complex formation. Solid products of naproxen with hydroxypropyl-beta-cyclodextrin, and/or arginine, prepared by different methods, were characterized by Differential Scanning Calorimetry (DSC), Hot Stage Microscopy (HSM) and Scanning Electron Microscopy (SEM).

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2003

Development and characterization of naproxen-chitosan solid systems with improved drug dissolution properties.

The solubilizing and amorphizing properties toward naproxen (a poorly water-soluble antiinflammatory drug) of chitosan, an emerging pharmaceutical biopolymer, have been investigated. Solid binary systems at different drug/polymer ratios have been prepared according to different techniques (mixing, cogrinding, kneading, coevaporation) using chitosan at low (CS-L(w)) and medium (CS-M(w)) molecular weight, and tested for dissolution properties. Drug-carrier interactions were investigated in both the liquid and solid state, by phase solubility analysis, differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy, and scanning electron microscopy. Drug dissolution parameters improved with increasing the polymer amount in the mixture, reaching the highest values at the 1:9 (w/w) drug/polymer ratio, and CS-L(w) was more efficacious than CS-M(w). Cogrinding was the most effective technique, showing the strongest amorphizing effect toward the drug and enabling an increase of more than ten times its relative dissolution rate. Coground mixtures at 3:7 (w/w) drug/polymer ratio were able to give directly compressed tablets which maintained unchanged the improved drug dissolution properties. Enhancer dissolution properties combined with its direct compression feasibility and antiulcerogenic action make CS-L(w) an optimal carrier for developing fast-release oral solid dosage forms of naproxen.

Adjuvants, Pharmaceutic↗
PubMed2003

In vitro release of sodium diclofenac from a central core matrix tablet aimed for colonic drug delivery.

The present study was aimed at developing a novel sodium diclofenac formulation for colonic release. The proposed delivery system consisted in a polymeric matrix tablet containing a drug central core purposely designed for obtaining a time-controlled release profile characterized by an initial phase of lag-time followed by a controlled release phase, according to zero order kinetics. The spheric central core was formed by a solid dispersion of the drug into the hydrophilic polymer PEG 4000, which enabled an improvement of drug dissolution properties with respect to other carriers such as lactose. Eudragit RS100 was used as inert polymeric matrix for the core coating, mixed (50:50, w/w) with sodium chloride and Emdex as channeling agents. Tablets containing the drug central core were prepared by direct compression, without any other excipient, and tested for dissolution properties according to the USP paddle method, under pH-gradient conditions. For both series of formulations, lag times increased with decreasing the channeling agent particle size, as a consequence of the smaller pores formed by its dissolution. However, formulations containing sodium chloride always showed longer lag times than the corresponding with Emdex and were more effective in providing prolonged zero-order release periods. This was mainly attributed to the plastic deformation properties under compression shown by sodium chloride, leading to a less porous, more compact network which more strictly controlled solvent penetration and drug dissolution and release rates. By varying the sodium chloride/Eudragit w/w ratio, it was possible to suitably modulate the length of both the lag time (for achieving colonic targeting) and zero-order release phases.

Administration, Oral↗
PubMed2003

Development of enteric-coated pectin-based matrix tablets for colonic delivery of theophylline.

The present work was aimed at developing a new colonic drug delivery system which takes advantage of the combined approaches of a specifically colon-biodegradable pectin matrix with a pH-sensitive Eudragit S100 polymeric coating. The developed system was able to suitably retard the onset of drug release and to provide a colon-specific delivery, thus overcoming the problems of pectin solubility in the upper gastrointestinal tract and low site-specificity of simple pH-dependent systems. Due to the poor compactability properties of pectin, it was used in mixture with Emdex, a hydrophilic directly-compressible material, in order to make it possible to prepare tablets by direct compression. Theophylline (TP) was used as model drug due to its suitable pharmacokinetic properties for colonic delivery and good absorption in the large intestine. The effects of varying the type of pectin (low and high methoxylated, or amidated), the pectin:Emdex ratio and the level of the pH-dependent polymeric coating on drug release behavior were investigated. Release tests were performed using sequential liquids simulating the physiological variation of pH and the effect of the presence or not of pectinolytic enzymes into the simulated colonic medium was evaluated. Thirty percent (w/w) was the the minimum content of Emdex for obtaining directly compressible tablets with sufficient hardness to withstand the coating process and 27% (w/w) was the minimum coating amount for obtaining an adequate lag time before the onset of drug release. After lag time, linear nearly zero-order profiles were obtained whose slope (i.e. the drug release rate) depended on both the Emdex content and the pectin type. Comparison of the results obtained in the presence or not of pectynolitic enzymes allowed selection of the high methoxylated pectin as the most interesting candidate for specific colonic delivery since it was the least water-soluble and the most susceptible to enzymatic degradation, thus assuring a greater site-specificity of drug release. Finally, the importance of using appropriate dissolution test conditions to adequately characterize the drug release profiles from delivery systems endowed with a microflora-activated drug release triggering mechanism has been demonstrated.

Bronchodilator Agents↗