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Sistemi matriciali per il rilascio prolungato di farmaci
No full text“Prolonged release matrix systems”
In the field of extended release dosage forms, hydrophilic matrices represent a subject of constant development with special relevance to the mechanism which rules over drug release kinetics. When such systems come into contact with water they swell as a consequence of polymeric chains relaxation and solvent diffusion; when water concentration exceeds a certain value the polymer undergoes a phase transition from a glassy to a rubbery state. This transition takes place at the swelling front. The primary aim of this work was to develop a simple and reliable model in which, by applying an impermeable film to the surface of the tablet and leaving only one base uncovered, the area of the swelling front can be considered almost constant during the entire release process. Moreover, this area can be easily determined. Therefore, many parameters directly related to the drug itself (solubility, particle size, formulation content) were investigated in order to evaluate their influence on the release rate using the area held by the active principle at the swelling front as a tool for analyzing drug release. A different process for matrix preparation was investigated, hot-melt extrusion, and compared with the most commonly used direct compression method. The results obtained with this strategy can open new and interesting topics requiring further investigation
Contenitori capsulari gastroresistenti realizzati mediante Injection Molding: valutazione preliminare del comportamento in vivo
No full textRecentemente sono stati proposti contenitori capsulari gastroresistenti a base di idrossipropilmetilcellulosa acetato succinato (HPMCAS) realizzati mediante la tecnica di injection molding (IM) [1]. Attraverso la messa a punto di una formulazione contenente, in aggiunta al polimero termoplastico, un plasticizzante e uno o più agenti canalizzanti (polimeri solubili e/o disgreganti) sono stati ottenuti sistemi con promettenti caratteristiche fisico-meccaniche e capaci di determinare soddisfacenti performance di rilascio in vitro. Nel presente lavoro è stato preliminarmente valutato il comportamento in vivo di capsule con pareti di spessore pari a 600 μm e contenenti il 30% di un disgregante (formulazione del contenitore: HPMCAS/polietilenglicole 1500/Explotab® CLV 55/22/23).
Sono stati condotti due differenti studi che hanno coinvolto nove volontari sani. Il primo studio ha previsto la somministrazione di un sistema assemblato, costituito da una capsula di HPMC in commercio (size 000) rivestita da un film gastroresistente, contenente antipirina come tracciante e un contenitore capsulare di HPMCAS ottenuto per IM e riempito, a sua volta, con paracetamolo. La capsula esterna di questo sistema dovrebbe rapidamente dissolvere dopo lo svuotamento gastrico rilasciando il suo duplice contenuto; la comparsa dell’antipirina e del paracetamolo nel fluido biologico in analisi dovrebbero quindi indicare l’apertura, rispettivamente, del sistema assemblato e del contenitore di HPMCAS. Nel secondo studio, invece, sono state co-somministrate un’unità stampata a base di HPMCAS, sempre contenente paracetamolo, e una capsula di HPMC in commercio, di analoghe dimensioni (size 0), contenente antipirina e rivestita da un film gastroresistente. I principi attivi utilizzati per il riempimento sono stati selezionati perché possono essere contemporaneamente rilevati nella saliva grazie ad un metodo HPLC a gradiente precedentemente messo a punto.
Tutte le tipologie di sistemi utilizzate per gli studi in vivo sono state testate anche in vitro allo scopo di verificarne il funzionamento dimostrando il comportamento atteso: il rilascio di antipirina dai sistemi assemblati e dalle capsule convenzionali rivestite per filmatura è avvenuto pochi minuti dopo il cambio di pH da 1,2 a 6,8 (Dissolution test for delayed-release dosage forms, Metodo B, USP 35) mentre è stata osservata una latenza prima del rilascio di circa 40-45 minuti nel caso delle capsule stampate, che può essere attribuita al loro maggior spessore. Per quanto riguarda le prove in vivo il tempo di prima comparsa in saliva dell’attivo contenuto in ciascun tipo di capsula è stato utilizzato come indicatore del tempo di apertura della stessa. Nel caso dei sistemi assemblati è stato calcolato un tempo medio di 117 minuti (CV 43,9) tra la comparsa dell’antipirina e quella del paracetamolo, che può essere considerato come il tempo necessario per la dissoluzione/disgregazione nell’intestino, e quindi l’apertura, della capsula stampata a base di HPMCAS. Attraverso la co-somministrazione, invece, delle capsule ottenute per IM e di quelle tradizionali rivestite con il film gastroresistente, è stato possibile osservare una differenza media di soli 35 minuti nella comparsa dei rispettivi traccianti. Tali risultati sono complessivamente in accordo con i dati riportati in letteratura riguardanti le forme gastroresistenti, che indicano generalmente un tempo di completa dissoluzione/disgregazione del film attorno alle 2 ore.
In conclusione le capsule a base di HPMCAS preparate per IM e riempite con un tracciante in polvere si sono dimostrate in grado di rilasciare il loro contenuto a livello intestinale. I risultati ottenuti appaiono incoraggianti se confrontati con sistemi gastroresisteniti preparati per filmatura. Nonostante lo spessore molto maggiore della barriera costituita dai sistemi stampati rispetto a quella presente nelle forme rivestite, infatti, la loro performance risulta paragonabile, indicando la possibilità di utilizzo delle capsule proposte in alternativa ai sistemi tradizionali.
1 L. Zema, G. Loreti, A. Melocchi, A. Maroni, L. Palugan, A. Gazzaniga. Gastroresistant capsular device prepared by injection molding. Int. J. Pharm. 440, 264-272, 201
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Development of an im mold purposely devised for an oral pulsatile-release capsular device
No full textInjection molding (IM) was recently proposed as the manufacturing technique for the preparation of an oral capsular device (ChronocapTM) based on hydroxypropyl cellulose (HPC) and intended for pulsatile and/or colonic delivery. By employing a prototype mold, it was possible to obtain capsules able to impart a lag phase to the release of a model drug, both in vitro and in vivo, the duration of which was dependent on the shell thickness and composition [1,2]. As some technical limitations were encountered with respect to the mold, manufacturing process and molded items, the aim of the present work was the development of a novel mold to enhance the industrial scalability of the ChronocapTM pulsatile delivery device.
Preliminarily, a formulation was selected composed of HPC (Klucel® LF) plasticized with polyethylene glycol 1500, and the relevant thermal, rheological and mechanical characteristics were in-depth evaluated. The need for a plasticizer was confirmed and its amount was related to the IM processability and mechanical stability of the molded items. Moreover, potential risks connected with the operating temperatures and heating time of the material were highlighted. Based on the results obtained, some changes were introduced into the press (e.g. reduced diameters of the piston and nozzle) and a novel mold was designed with several improved features (e.g. hot runner and consistent/reduced flow length in all directions). After adjusting the process parameters a fully automated manufacturing process was achieved with a cycle time reduced to about 5 s and no need for lubricants. The capsular devices prepared demonstrated good technological properties and improved reproducibility of the shell thickness, mechanical properties as well as release performance.
[1] A. Gazzaniga et al., AAPS PharmSciTech 12, 295-303, 2011;
[2] A. Gazzaniga et al., 38th CRS annual meeting & exposition July 30 - August 3, National Harbor, Maryland
Development of a mold for capsule-shaped oral pulsatile delivery devices
No full textINTRODUCTION
In a recent work, the feasibility of injection-molding (IM) in the preparation of a shell device (ChronocapTM) for oral pulsatile delivery and/or time-dependent colonic release was demonstrated [1]. Capsular devices based on hydroxypropyl cellulose (HPC) showed the ability to delay, both in vitro and in vivo, the release of tracer drug powder as a function of the wall thickness and polymeric composition of the shell [1,2].
The mold prototype used offered several advantages, such as the preparation of matching caps and bodies within a single manufacturing cycle as well as of devices with differing nominal shell thicknesses of the thinner wall areas, e.g. the regions where body and cap were not overlapped because of the locking system. However, some limitations were highlighted with respect to the resulting device, such as the variability in the shell thickness and its poor consistency with the nominal value. Moreover, the rate of production and automation extent of the manufacturing process could be improved.
The aim of the present work was therefore the design of a special mold, dedicated to the production of HPC-based capsules, and the subsequent development of a manufacturing process able to enhance the industrial scalability of this pulsatile delivery device.
EXPERIMENTAL METHODS
Materials -Hydroxypropyl cellulose (HPC, Klucel®LF, Aqualon, US; Eigenmann&Veronelli, I); polyethylene glycol (PEG1500, Clariant Masterbatches, I); acetaminophen (AAP, C.F.M., I).
Rheological characterization -A rotational rheometer (ARES-2K, TA instruments, US) was used both in the temperature range of 180-280°C (gap=1mm; frequency=10rad/s; strain=0,1%; measures after 6min) and in isotherm (time from 0 to 1400sec; frequency=10rad/s; strain=0,2%; measures after 3min).
Injection-molding process -A mixture of HPC 90% and PEG1500 10% was prepared in Turbula (Type T2C, WAB, CH), dried in a ventilated oven for 24 h at 40°C and then transferred into the injection-molding press (Baby Plast mod. 6/10P, Cronoplast E; Rambaldi S.r.l., I). IM process conditions are reported within the Results.
In vitro release test – Each capsule body was manually filled with 80mg of acetaminophen powder, closed with a matching cap an sealed by applying a 3% w/v Klucel®LF aqueous solution to the junction area. A six-position USP34 disintegration apparatus was used; each unit was inserted in a basket-rack assembly (only one tube occupied) moving at 31 cycles/min in separate vessels with 900mL of deionized water (37±5°C) [3]. Fluid samples were assayed spectrophotometrically at 248nm. Lag time, i.e. the time to 10% release, and pulse time, i.e. the time elapsed between 90 and 10% release, were calculated from the release curves (n=6).
RESULTS AND DISCUSSION
An IM capsular shell with thickness of few hundreds μm and length as well as height around 10mm would fall within the definition of micromolded products [4]. Microinjection molding (μIM) is not only a simple scale-down of classical IM but also involves radical changes in machines, mold construction and raw materials. In particular, mold design, formulation development and setup of process parameters (e.g. mold temperature, injection speed and pressure, holding time and pressure) should be carried out concomitantly. However, formulation changes (e.g. percentage of plasticizer) at the current stage of development of the pulsatile delivery capsular device might impair the physical stability, release performance or mechanical characteristics. Therefore, in order to develop a robust manufacturing process, we focused on an in-depth evaluation of thermal, rheological and mechanical characteristics of the HPC-based formulation previously established (90% Klucel®LF and 10% PEG 1500, i.e. reference formulation) [1].
In the range of operating temperatures, the polymer viscosity tended to increase, which could be attributed to a possible rearrangement of the polymeric chains promoted by water loss (Fig. 1).
Figure 1: absolute viscosity of Klucel®LF (green) and reference formulation (blue).
Viscosity started decreasing only beyond 200oC, that is at temperatures that cannot be exploited because of the polymer degradation. The viscosity of the polymeric reference formulation showed an analogous trend though it was always lower with respect to the polymer alone and seemed to be less affected by the hypothesized macromolecular chain rearrangement. Moreover, the formulation viscosity under isothermal conditions (T=190°C) demonstrated a tendency to increase over time (Fig. 2).
These results confirmed the need for dealing with a plasticized formulation and indicated that not only operating temperatures, especially over 170-180°C, can be a critical issue, but also the time over which the material is maintained at this temperature, that can be correlated with the process cycle time.
Figure 2: rheological parameters of the reference formulation: absolute viscosity (red), G’ storage modulus (blue), G’’ loss modulus (green), G’’/G’ (black).
In order to avoid the polymer overheating, some changes were introduced into the press machine (piston and nozzle diameters were reduced), and the use of a hot runner was envisaged to allow the molten material to be heated until the cavity image port is reached. Finally, a new mold was designed, of constant 600μm nominal thickness, comprising the hot runner and two interchangeable inserts for the production of cap or body items. The improved characteristics of the mold are: i) central position of the injection orifice to allow a consistent flow length in all directions; ii) halved thickness in the overlapping end portions to ensure a constant thickness of the closed device; iii) length/diameter ratio reduced to 1.5; iv) inserted air ejection mechanism that prevents the need for lubricants.
For the final rectification of the mold, mechanical tests were performed on the formulation, in order to verify its tendency to undergo dimensional changes after IM processes in different ranges of temperatures (shrinkage test, data not reported).
Table I: IM process conditions
Plasticating temperature; °C 100
Injecting temperature; °C 130
Nozzle temperature; °C 140
Hot runner temperature; °C 160
First injection pressure; bar 30
First injection time; s 0.5
Second injection pressure; bar 10
Second injection time; s 0.3
Cooling temperature; °C 15
Cooling time; s 2.5
Total cycle time; s 5
By the proper selection of operating parameters (Table I) it was possible to achieve a completely automated IM manufacturing process with a cycle time of about 5s for each item (cap or body), avoiding the use of internal or external lubrication. The technical drawing of the capsular device is reported in Figure 3.
Figure 3: technical drawing of the capsular device.
Because major changes were introduced into the system design, the capsule shells manufactured by the novel mold needed to be evaluated in terms of technological properties and release performance (Table II and Fig. 4).
Table II: technological characteristics of the capsular devices (CV in brackets)
weight; mg 228 (0.51)
thickness; μm 610 (3.30)
elastic modulus; N/mm2 3.509 (2.01)
Figure 4: release profiles from capsular devices (average lag and pulse time in frame; standard deviation in brackets).
The capsular devices prepared by the new mold demonstrated good technological properties and, as compared with the previous systems, improved reproducibility of shell thickness, mechanical properties, opening mechanism as well as release performance.
AKNOWLEDGEMENTS
The authors would like to thank Consorzio Proplast for technical support.
REFERENCES
[1] A. Gazzaniga et al., AAPS Pharm .Sci. Tech. 12(1), 295-303, 2011
[2] A. Gazzaniga et al., 38th CRS annual meeting and exposition, august 2011
[3] A. Gazzaniga et al., STP Pharm. Sci. 5, 83-88, 1995
[4] J. Giboz et al., J. Micromech. Microeng. 17, R96-R109, 200
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Piattaforme di rilascio orali in forma di contenitori funzionali realizzate mediante injection molding
No full textI sistemi di rilascio somministrati oralmente si avvalgono di strategie formulative/tecnologiche per aumentare la biodisponibilità o modificare la cessione del principio attivo in termini di velocità, tempo o sito. Una delle configurazioni in cui più spesso si presentano è costituita da un nucleo contenente il farmaco rivestito con materiali polimerici dotati di specifiche proprietà che ne caratterizzano il comportamento e/o ne definiscono l’applicazione (es. sistemi gastroresistenti, reservoir). In una prospettiva di industrializzazione, sarebbe particolarmente vantaggioso poter svincolare lo sviluppo formulativo dell’elemento di controllo del rilascio, ovvero la barriera polimerica esterna, da quello del core contenente l’attivo. In quest’ottica appare molto promettente la tecnica di injection molding (IM) che prevede l’iniezione di materiale opportunamente rammollito (movimentazione e riscaldamento) in uno stampo che gli conferisce una forma tridimensionale definita. Sulla base delle proprietà funzionali (solubilità pH-dipendente, capacità di rigonfiamento e dissoluzione/erosione, permeabilità) sono stati selezionati una serie di materiali polimerici di comune impiego farmaceutico (HPMCAS, HPC, EC) con i quali valutare la fattibilità di realizzazione di una gamma di piattaforme di rilascio. Si tratta di contenitori in forma capsulare, ovvero di sistemi adatti ad essere riempiti con varie tipologie di formulazioni, capaci di determinare la performance di rilascio dell’attivo veicolato sulla base, esclusivamente, delle caratteristiche di composizione (natura del polimero) e spessore delle pareti. In particolare, vengono presentati risultati relativi alla lavorabilità dei materiali e alle caratteristiche tecnologiche e di performance di capsule gastroresistenti e a rilascio ritardato o prolungato
Film coatings for oral pulsatile release
No full textPulsatile delivery is generally intended as a release of the active ingredient that is delayed for a programmable period of time to meet particular chronotherapeutic needs and, in the case of oral administration, also target distal intestinal regions, such as the colon. Most oral pulsatile delivery platforms consist in coated formulations wherein the applied polymer serves as the release-controlling agent. When exposed to aqueous media, the coating initially performs as a protective barrier and, subsequently, undergoes a timely failure based on diverse mechanisms depending on its physico-chemical and formulation characteristics. Indeed, it may be ruptured because of the gradual expansion of the core, swell and/or erode due to the glassy-rubbery polymer transition or become permeable thus allowing the drug molecules to diffuse outwards. Otherwise, when the coating is a semipermeable membrane provided with one or more orifices, the drug is released through the latter as a result of an osmotic water influx. The vast majority of pulsatile delivery systems described so far have been prepared by spray-coating, which offers important versatility and feasibility advantages over other techniques such as press- and dip-coating. In the present article, the design, manufacturing and performance of spray-coated pulsatile delivery platforms is thus reviewed
X-Ray Computed Microtomography for the Study of Modified Release Systems
No full textIn this brief article, the use of X-ray computed microtomography (CMT) for the visualization of the three-dimensional structure of pharmaceutical material is discussed. CMT is a non-destructive technique, which provides cross-sectional images based on local X-ray attenuation. The X-ray attenuation is then related to the material density. The results are discussed specifically with reference to the dissolution profile of a modified release tablet (Adalat OROS) at specific time points. This novel technique is complementary to standard compendial pharmaceutical tests, since it integrates information from several experimental methods to provide a more complete picture of specific drug-delivery systems
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