M. E. Sangalli

Drug release modulation by physical restrictions of matrix swelling

Abstract Swellable matrix systems with anomalous release kinetics are suitable solutions for drug release control for oral administration. Generally, the release rate modulation is achieved through the use of different types of polymer or the employment of soluble or insoluble fillers. The resulting release mechanism depends on the relative importance of tablet relaxation and drug diffusion rates. By adjusting these two rates, it is possible simultaneously to control the release mechanism and the release rate. In this work, we present the results obtained by changing the relaxation rate of the matrix by means of the application of impermeable coatings that partially cover the matrix. The applied impermeable coating modifies the relaxation rate of the matrix by affecting the dimension of the swelling of the plain matrix while leaving the diffusion characteristics of the drug practically intact. The overall result is that the original kinetics of the uncoated matrix is shifted towards constant release, dependent on the extension and position of the impermeable coating.

In vitro and in vivo evaluation of an oral system for time and/or site-specific drug delivery.

Aim of this work was the evaluation of an oral system (Chronotopic) designed to achieve time and/or site-specific release. The system consists in a drug-containing core, coated by a hydrophilic swellable polymer which is responsible for a lag phase in the onset of release. In addition, through the application of an outer gastroresistant film, the variability in gastric emptying time can be overcome and a colon-specific release can be sought relying on the relative reproducibility of small intestinal transit time. For this study, cores containing antipyrine as the model drug were prepared by tableting and both the retarding and enteric coatings were applied in fluid bed. The release tests were carried out in a USP 24 paddle apparatus. The in vivo testing, performed on healthy volunteers, envisaged the HPLC determination of antipyrine salivary concentration and a gamma-scintigraphic investigation. The in vitro release curves presented a lag phase preceding drug release and the in vivo pharmacokinetic data showed a lag time prior to the detection of model drug in saliva. Both in vitro and in vivo lag times correlate well with the applied amount of the hydrophilic retarding polymer. The gamma-scintigraphic study pointed out that the break-up of the units occurred in the colon. The obtained results showed the capability of the system in delaying drug release for a programmable period of time and the possibility of exploiting such delay to attain colon-targeted delivery according to a time-dependent approach.

Time-controlled oral delivery systems for colon targeting

In recent years, many research efforts have been spent in the achievement of selective delivery of drugs into the colon following oral administration. Indeed, colonic release is regarded as a beneficial approach to the pharmacological treatment or prevention of widespread large bowel pathologies, such as inflammatory bowel disease and adenocarcinoma. In addition, it is extensively explored as a potential means of enhancing the oral bioavailability of peptides, proteins and other biotechnological molecules, which are known to be less prone to enzymatic degradation in the large, rather than in the small, intestine. Based on these premises, several formulation strategies have been attempted in pursuit of colonic release, chiefly including microflora-, pH-, pressure- and time-dependent delivery technologies. In particular, this review is focused on the main design features and release performances of time-controlled devices, which rely on the relative constancy that is observed in the small intestinal transit time of dosage forms.

Oral pulsatile drug delivery systems.

In the field of modified release, there has been a growing interest in pulsatile delivery, which generally refers to the liberation of drugs following a programmable lag phase from the time of administration. In particular, the recent literature reports on a variety of pulsatile release systems intended for the oral route, which have been recognised as potentially beneficial to the chronotherapy of widespread diseases, such as bronchial asthma or angina pectoris, with mainly night or early morning symptoms. In addition, time-dependent colon delivery may also represent an appealing related application. The delayed liberation of orally administered drugs has been achieved through a range of formulation approaches, including single- or multiple-unit systems provided with release-controlling coatings, capsular devices and osmotic pumps. Based on these premises, the aim of this review is to outline the rational and prominent design strategies behind oral pulsatile delivery.

Feasibility, stability and release performance of a time-dependent insulin delivery system intended for oral colon release.

The aim of the present work was to evaluate the viability of a time-dependent delivery platform (Chronotopic) in preparing an insulin-based system intended for oral colon delivery. The main objectives were to assess the influence of the manufacturing process and storage conditions on the protein stability. Insulin-loaded cores were manufactured by direct compression and were subsequently coated with hydroxypropyl methylcellulose (HPMC) in a top-spray fluid bed up to increasing weight gains, namely 20%, 60% and 100%. In order to evaluate the impact the operating conditions may have on the protein integrity, insulin and its main degradation products (A21-desamido insulin -A21, Other Insulin-Related Compounds -OIRCs, and High-Molecular Weight Proteins -HMWPs) were assayed on samples collected after each process step by chromatographic methods. Furthermore, long-term (4 degrees C) and accelerated (25 degrees C-60% RH) stability studies were carried out on tablet cores and coated systems by assessing insulin, A21, OIRC and HMWP percentages throughout a one-year storage period. In addition, the in vitro release behaviour was investigated during the same study period. The overall results indicated that the manufacturing process is not detrimental for insulin integrity and that 4 degrees C storage temperature alters neither the protein content nor the release performances of the device. It was therefore concluded that insulin-containing systems intended for oral colon delivery can be obtained by the Chronotopic technology.

Influence of betacyclodextrin on the release of poorly soluble drugs from inert and hydrophilic heterogeneous polymeric matrices

The release behavior of poorly soluble drugs (naproxen and ketoprofen) from inert (acrylic resins) and hydrophilic swellable (high-viscosity hydroxypropylmethylcellulose) tableted matrices containing betacyclodextrin (betaCD) was investigated. The results demonstrated that, in both cases, betaCD can enhance the rate of drug release. Matrices obtained from formulations in which lactose replaced betaCD were also evaluated. BetaCD in inert matrices causes a dramatic increase in the rate of drug release, higher than that promoted by lactose which merely acts as a channelling agent. This result suggests that possible in situ formation of the drug-betaCD complex. which causes an improvement in apparent drug solubility, could have a greater influence on the rate of drug release than the possible increase of water uptake by a soluble filler. Indeed, if the opposite were true, lactose would be more effective in increasing the rate of drug release than betaCD, because of its greater solubility in water. On the contrary, in the case of hydrophilic matrices, lactose proves to be much more effective in promoting drug release than betaCD. It seems that, while the bulky interaction compound can freely diffuse through water-filled pores of inert systems, its diffusion through swollen macromolecular chains of hydrophilic matrices may be hindered. This hypothesis was supported by data obtained from binary (drug/polymer) and ternary (drug/polymer/betaCD) hydrophilic matrices using a betaCD-containing dissolution media.

Oral delivery system for two‐pulse colonic release of protein drugs and protease inhibitor/absorption enhancer compounds

It is well known that the intestinal stability and absorption of protein drugs are improved when enzyme inhibitors/permeation enhancers are coadministered. Recently, it was hypothesized that an increased effectiveness of these adjuvants might be achieved by timing their release prior to that of the protein, so that a more favorable environment would be established in advance. Therefore, an oral system was proposed for two-pulse colonic release of insulin and the protease inhibitor camostat mesilate/absorption enhancer sodium glycocholate. The device consisted of a drug-containing core, an inner swellable/erodible low-viscosity hydroxypropyl methylcellulose (HPMC) coating, an intermediate adjuvant layer, and an additional outer HPMC coating. HPMC coats and camostat mesilate/sodium glycocholate films with differing thicknesses were applied to immediate-release tablet cores by aqueous spray coating. The obtained units were characterized for weight, thickness, breaking force, and release performance. All systems showed satisfactory technological properties and the pursued pulsatile delivery behavior, with programmable delay phases preceding inhibitor/enhancer release and elapsing between inhibitor/enhancer and protein release, respectively. Indeed, both lag times linearly correlated with the relevant HPMC coating level. The system was thus proven suitable for yielding two-pulse release profiles, in which lag phases could be modulated to provide convenient concentration patterns for proteins and adjuvants.

Solid-state characterization of paracetamol metastable polymorphs formed in binary mixtures with hydroxypropylmethylcellulose

Two metastable polymorphs of paracetamol (forms II and III) were prepared by appropriate thermal methods from binary mixtures containing 10% (w/w) of hydroxypropylmethylcellulose. By controlling the reheating step, it was possible to address the recrystallization of the drug either into form II or III. Moreover, it was observed that form III transforms either into form II or I depending on the preparation method. The physical characterization of the polymorphs was performed by means of micro-Fourier transform infrared spectroscopy (MFTIR) and powder X-ray diffractometry (PXRD), both temperature controlled.

Preparation and evaluation of an oral delivery system for time-dependent colon release of insulin and selected protease inhibitor and absorption enhancer compounds

The aim of this work was to prepare and evaluate an oral dosage form intended for time-dependent colon delivery of insulin along with a selected protease inhibitor (camostat mesilate) and absorption enhancer (sodium glycocholate). A previously described release platform, which had proven potentially suitable for the protein delivery, was exploited. Insulin compatibility with the above-mentioned adjuvants was preliminarily evaluated. For this purpose, the drug and its main degradation products were assayed by HPLC in insulin powder mixtures with camostat mesilate and/or sodium glycocholate stored 12 months at 4 degrees C. No significant decrease in protein content or increase in degradation product percentages beyond Eur. Ph. 6th Ed. limits was highlighted. Moreover, calorimetric studies performed on physical and compacted binary insulin mixtures with camostat mesilate and sodium glycocholate showed that the thermal behavior of both adjuvants was unchanged. Subsequently, tablet cores with differing compositions were prepared and spray-coated with an aqueous HPMC solution in order to obtain pulsatile delivery systems. The coated units were demonstrated to concurrently release the drug and the adjuvants in a prompt and quantitative mode after consistent lag times. Based on these results, the device was proven a potential candidate for colon delivery of insulin and the selected adjuvants.

The Use of β-Cyclodextrin as a Pelletization Agent in the Extrusion/ Spheronization Process

The use of beta-cyclodextrin for the preparation of pellets by the extrusion/spheronization process is described for different formulations and processing conditions. Sieve analysis and friability tests were performed to assess the physical and technological characteristics of pellets. Satisfactory products were obtained with beta-cyclodextrin contents up to 90% by weight.