Alessandra Maroni

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.

Oral colon delivery of insulin with the aid of functional adjuvants

Oral colon delivery is currently considered of importance not only for the treatment of local pathologies, such as primarily inflammatory bowel disease (IBD), but also as a means of accomplishing systemic therapeutic goals. Although the large bowel fails to be ideally suited for absorption processes, it may indeed offer a number of advantages over the small intestine, including a long transit time, lower levels of peptidases and higher responsiveness to permeation enhancers. Accordingly, it has been under extensive investigation as a possible strategy to improve the oral bioavailability of peptide and protein drugs. Because of a strong underlying rationale, most of these studies have focused on insulin. In the present review, the impact of key anatomical and physiological characteristics of the colon on its viability as a protein release site is discussed. Moreover, the main formulation approaches to oral colon targeting are outlined along with the design features and performance of insulin-based devices.

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.

Hot-melt extruded filaments based on pharmaceutical grade polymers for 3D printing by fused deposition modeling

Fused deposition modeling (FDM) is a 3D printing technique based on the deposition of successive layers of thermoplastic materials following their softening/melting. Such a technique holds huge potential for the manufacturing of pharmaceutical products and is currently under extensive investigation. Challenges in this field are mainly related to the paucity of adequate filaments composed of pharmaceutical grade materials, which are needed for feeding the FDM equipment. Accordingly, a number of polymers of common use in pharmaceutical formulation were evaluated as starting materials for fabrication via hot melt extrusion of filaments suitable for FDM processes. By using a twin-screw extruder, filaments based on insoluble (ethylcellulose, Eudragit(®) RL), promptly soluble (polyethylene oxide, Kollicoat(®) IR), enteric soluble (Eudragit(®) L, hydroxypropyl methylcellulose acetate succinate) and swellable/erodible (hydrophilic cellulose derivatives, polyvinyl alcohol, Soluplus(®)) polymers were successfully produced, and the possibility of employing them for printing 600μm thick disks was demonstrated. The behavior of disks as barriers when in contact with aqueous fluids was shown consistent with the functional application of the relevant polymeric components. The produced filaments were thus considered potentially suitable for printing capsules and coating layers for immediate or modified release, and, when loaded with active ingredients, any type 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.

Injection Molding and its application to drug delivery

Injection Molding (IM) consists in the injection, under high pressure conditions, of heat-induced softened materials into a mold cavity where they are shaped. The advantages the technique may offer in the development of drug products concern both production costs (no need for water or other solvents, continuous manufacturing, scalability, patentability) and technological/biopharmaceutical characteristics of the molded items (versatility of the design and composition, possibility of obtaining solid molecular dispersions/solutions of the active ingredient). In this article, process steps and formulation aspects relevant to IM are discussed, with emphasis on the issues and advantages connected with the transfer of this technique from the plastics industry to the production of conventional and controlled-release dosage forms. Moreover, its pharmaceutical applications thus far proposed in the primary literature, intended as either alternative manufacturing strategies for existing products or innovative systems with improved design and performance characteristics, are critically reviewed.

Film coatings for oral colon delivery

Oral colon delivery is pursued through a number of formulation strategies with the aim of enabling effective and well-tolerated treatments for large bowel pathologies or enhancing the intestinal absorption of peptide and protein drugs. According to such strategies, coated dosage forms for colonic release may be provided with microbiota, pH, pressure or time-dependent polymeric films. Microbiota-activated coatings are mostly obtained from polysaccharides of natural origin mixed with insoluble structuring excipients. Alternatively, synthetic azo compounds have been employed, generally requiring organic solvents for use as spray-coating agents. On the other hand, pH-sensitive films show responsiveness to pH changes in the lower gut, such as the rise generally observed in the terminal ileum and distal colon or the slight acidification of caecal contents by bacterial fermentation products. Pressure-sensitive coatings are intended for rupturing because of the relatively elevated pressure that may affect solid dosage forms in the large bowel. Finally, time-dependent films are expected to undergo timed erosion, break-up or permeabilization processes irrespective of the aforementioned physiological variables. In this review, the differing films applied for colon delivery purposes are surveyed, and details on their composition, manufacturing and performance are reported.

Oral pulsatile delivery: rationale and chronopharmaceutical formulations.

Oral pulsatile/delayed delivery systems are designed to elicit programmable lag phases preceding a prompt and quantitative, repeated or prolonged release of drugs. Accordingly, they draw increasing interest because of the inherent suitability for accomplishing chronotherapeutic goals, which have recently been highlighted in connection with a number of widespread chronic diseases with typical night or early-morning recurrence of symptoms (e.g. bronchial asthma, cardiovascular disease, rheumatoid arthritis, early-morning awakening). In addition, time-based colonic release can be attained when pulsatile delivery systems are properly adapted to overcome unpredictable gastric emptying and provide delay phases that would approximately match the small intestinal transit time. Oral pulsatile delivery is pursued by means of a variety of release platforms, namely reservoir, capsular and osmotic devices. The aim of the present review is to outline the rationale and main formulation strategies behind delayed-release dosage forms intended for the pharmacological treatment of chronopathologies.

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.