A. Gazzaniga

Drug/Polymer Matrix Swelling and Dissolution

The swelling and dissolution behavior of pharmaceutical systems containing a drug and a polymer can be analyzed by a mathematical model which predicts the drug released and the gel layer thickness as a function of time. It is possible to approximate the values of several of the physicochemical parameters of this model in order to obtain an order-of-magnitude analysis of the tablet dissolution process. Selected experimental results of tablet dissolution and drug release are analyzed and conclusions are made about the importance of the drug and polymer content and solubility in the release behavior.

Oral delayed-release system for colonic specific delivery

Abstract The paper describes a novel oral time-based drug release system for colonic specific delivery. The system, designed to exploit the relatively constant small intestine transit time of dosage forms, consists of drug-containing cores coated with three polymeric layers. The outer layer dissolves at pH > 5, then the intermediate swellable layer, made of high-viscosity HPMC, interacts slowly with aqueous fluids, thus providing the delay phase. The inner film is made of an enteric material. The system provides the expected delayed release pattern, as also indicated by the preliminary in vivo experiments on rats.

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.

Swelling-activated drug delivery systems

A previous paper dealt with the preparation of an in vitro programmable zero-order drug delivery system in which the area of the surface exposed to the dissolution medium and the macromolecular relaxation of polymer controlled the release of the drug. In the present study, the preparation of similar delivery systems is described, in which differing drugs and polymers were used to ascertain the mechanism governing the drug-release kinetics. The movement of the interfaces between solvent and system was measured during drug release in systems with varying composition. The results indicate that the synchronization of the movement of swelling and eroding fronts at the solvent-system interface determines the achievement of the linear-release kinetics of such swelling activated systems and that the swelling and dissolution characteristics of the polymer employed for core preparation govern front movement.

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.

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.