In vitro and in vivo evaluation of a pH-, microbiota- and time-based oral delivery platform for colonic release.

Several formulation strategies have been proposed for oral colon delivery, particularly for the therapy of inflammatory bowel disease (IBD). However, targeting the large intestine remains a challenging goal. The aim of this study was to develop and evaluate a novel type of drug delivery system, which is based on multiple drug release triggers for reliable performance. The system consists of: (i) a drug core, (ii) an inner swellable low-viscosity hydroxypropyl methylcellulose (HPMC) layer, and (iii) an outer film coating based on a Eudragit® S:high-methoxyl (HM) pectin (7:3 w/w) blend, optionally containing chitosan. Convex immediate release tablets (2 or 4 mm in diameter) containing paracetamol or 5-aminosalicylic acid (5-ASA) were coated in a fluid bed. The double-coated tablets exhibited pulsatile release profiles when changing the release medium from 0.1 N HCl to phosphate buffer pH 7.4. Also, drug release was faster in simulated colonic fluid (SCF) in the presence of fecal bacteria from IBD patients compared to control culture medium from tablets with outer Eudragit® S: HM pectin: chitosan coatings. The latter systems showed promising results in the control of the progression of colitis and alteration of the microbiota in a preliminary rat study.

3D printed multi-compartment capsular devices for two-pulse oral drug delivery.

In the drug delivery area, versatile therapeutic systems intended to yield customized combinations of drugs, drug doses and release kinetics have drawn increasing attention, especially because of the advantages that personalized pharmaceutical treatments would offer. In this respect, a previously proposed capsular device able to control the release performance based on its design and composition, which could extemporaneously be filled, was improved to include multiple separate compartments so that differing active ingredients or formulations may be conveyed. The compartments, which may differ in thickness and composition, resulted from assembly of two hollow halves through a joint also acting as a partition. The systems were manufactured by fused deposition modeling (FDM) 3D printing, which holds special potential for product personalization, and injection molding (IM) that would enable production on a larger scale. Through combination of compartments having wall thickness of 600 or 1200µm, composed of promptly soluble, swellable/erodible or enteric soluble polymers, devices showing two-pulse release patterns, consistent with the nature of the starting materials, were obtained. Systems fabricated using the two techniques exhibited comparable performance, thus proving the prototyping ability of FDM versus IM.

Active packaging for topical cosmetic/drug products: a hot-melt extruded preservative delivery device.

A delivery device intended for the prolonged release of antimicrobial agents, able to enhance the stability profile of liquid/semi-solid cosmetic/pharmaceutical products for topical application, was proposed in the present study. With the aid of a simulation program based on compartment models, the relevant kinetic and formulation parameters were defined using dehydroacetic acid sodium salt (DHA.Na, Prevan) as the model preservative. Indeed, the overall DHA.Na degradation rate is increased in the presence of formaldehyde releasers that are often employed as co-preservatives. Inert matrices (3 g weight and 18 mm diameter) based on high-density polyethylene (HDPE), possibly consistent with the design of an active packaging meant for preservative delivery, were prepared by hot-melt extrusion. Units with satisfactory physical-technological properties could be obtained up to 50%w/w loads of antimicrobial agent. In an attempt to modify the relevant Fickian release profiles by varying the area exposed to the medium, matrix systems coated with an impermeable film except for one base (CMs) or for the inner surface of a central drilled hole (PCMs) were investigated. On the basis of the n exponent of power equation and the outcome of linear fitting, PCMs were proven able to yield the zero-order release behaviour needed to ensure constant DHA.Na levels over a predetermined time period, as indicated by the simulation process.

Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: an investigation into the mechanisms governing drug release.

When used as release-controlling coating agents for tableted core-based pulsatile delivery systems, three different hydroxypropyl methylcellulose (HPMC) grades, Methocel E5, E50, and K4M, provided lag phases of varying duration (Methocel K4M > E50 > E5) and a prompt and quantitative model drug release. Dissolution/mechanical erosion, permeability increase and disruption of the hydrated polymeric layer were assumed to participate in the definition of the overall release pattern. Based on these premises, we investigated what process(es) might prevail in the release-controlling mechanism for each HPMC grade. The polymers were evaluated for dissolution and swelling, while the finished systems were concomitantly evaluated for drug release and polymer dissolution. The obtained results indicated likely similarities between Methocel E5 and E50 performances, which we hypothesized to be mainly dissolution/erosion-controlled, and a clearly different behavior for Methocel K4M. This polymer indeed proved to yield higher viscosity and slower dissolving gel layer, which was able to withstand extensive dissolution/erosion for periods that exceeded the observed lag phases. The particular characteristics of swollen Methocel K4M were shown to be associated with possible drug diffusion phenomena, which might impair the prompt and quantitative release phase that is typical of pulsatile delivery.

Different HPMC viscosity grades as coating agents for an oral time and/or site-controlled delivery system: a study on process parameters and in vitro performances.

Currently, delayed/pulsatile release and colon delivery represent topics of remarkable interest. The present paper deals with the study and development of an oral dosage form devised to release drugs following a programmed time period after administration or, when opportune design modifications are introduced, to target the colon. The system is composed of a drug-containing core and a hydrophilic swellable polymeric coating capable of delaying drug release through slow interaction with aqueous fluids. An optional external gastroresistant film is applied to overcome gastric emptying variability, thus allowing colon delivery to be pursued according to the time-dependent approach. The aim of this work was to evaluate different hydroxypropyl methylcellulose (HPMC) viscosity grades as possible materials for the attainment of the system retarding hydrophilic layer. Both the relevant suitability for application onto tablet cores by aqueous spray-coating in fluid bed and capability of delaying drug release for a programmable period were explored and compared. Methocel E50 was found to afford the best balance among different important items, i.e. process time, retarding ability, dimensions of the coated units and possibility of finely tuning the delay duration. Further results pointed out the robustness of Methocel E50-based systems, which have shown to be practically unaffected by the concentration of the employed coating solution and the pH of the release medium, as well as only poorly influenced by ionic strength, at least with regard to values encompassed in the physiological range for gastrointestinal fluids.

Polymorphism of NCX4016, an NO-releasing derivative of acetylsalicylic acid.

NCX4016 [2-acetoxybenzoic acid 3'-(nitrooxymethyl)phenyl ester] is a recently developed nitrooxy-derivative of aspirin with improved antiinflammatory, analgesic, and antithrombotic activity as well as increased gastrointestinal safety. Systematic polymorphic screening performed with different solvents and preparation methods resulted in the identification of two polymorphs, designated Forms I and II. They were characterized by scanning electron microscopy, powder X-ray diffraction, thermal analyses, and infrared spectroscopy; the crystal structure of polymorph I was solved by single-crystal X-ray analysis and compared with that of aspirin. Finally, intrinsic dissolution rate studies and calculations according to the melting data method were performed to assess the thermodynamic relationship between the two polymorphs.

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.

Comparative in vitro evaluation of nimesulide-containing preparations on the Italian market.

Nimesulide is a quite popular non-steroidal anti-inflammatory drug (NSAID), which has been demonstrated to preferentially inhibit cycloxygenase-2 (COX-2), thus exerting milder gastrointestinal and renal side effects. Apart from the original products (Aulin and Mesulid), several copy and generic nimesulide-containing preparations are presently available on the Italian market. Generics are defined by the World Health Organization (WHO) as interchangeable multi-source pharmaceutical products and, according to international regulatory issues, their bioequivalence to an already marketed reference product has to be proven. Due to its physico-chemical properties, and in particular to the low solubility, nimesulide appears to be a critical molecule from a biopharmaceutical point of view. On the basis of these premises, the aim of the present work was to perform a comparative evaluation of tablets in vitro behaviour for the best-selling copy (Sulidamor) and generic (Nimesulide Dorom) in reference to the original products. The results provided by the dissolution test pointed out statistically significant differences in the in vitro behaviour displayed by the original products on one hand and by the copy as well as generic preparations in exam on the other.