RESUMEN
In order to expand the limited portfolio of available polymer-based excipients for fabricating three-dimensional (3D) printed pharmaceutical products, Lipid-based excipients (LBEs) have yet to be thoroughly investigated. The technical obstacle of LBEs application is, however their crystalline nature that renders them very brittle and challenging for processing via 3D-printing. In this work, we evaluated the functionality of LBEs for filament-based 3D-printing of oral dosage forms. Polyglycerol partial ester of palmitic acid and polyethylene glycols monostearate were selected as LBEs, based on their chemical structure, possessing polar groups for providing hydrogen-bonding sites. A fundamental understanding of structure-function relationship was built to screen the critical material attributes relevant for both extrusion and 3D-printing processes. The thermal behavior of lipids, including the degree of their supercooling, was the critical attribute for their processing. The extrudability of materials was improved through different feeding approaches, including the common powder feeding and a devised liquid feeding setup. Liquid feeding was found to be more efficient, allowing the production of filaments with high flexibility and improved printability. Filaments with superior performance were produced using polyglycerol ester of palmitic acid. In-house designed modifications of the utilized 3D-printer were essential for a flawless processing of the filaments.
Asunto(s)
Excipientes , Ácido Palmítico , Formas de Dosificación , Liberación de Fármacos , Ésteres , Excipientes/química , Polvos , Impresión Tridimensional , Comprimidos/química , Tecnología Farmacéutica/métodosRESUMEN
The aim of this work is a better understanding of solid lipid extrusion (SLE) for protein depot production using a lab-scale twin-screw (tsc)-extruder. In this context, little is known about the relationship of process parameters such as extrusion temperature, screw speed, or formulation on implant characteristics. It is difficult to attribute release characteristics to only one parameter, since the release will always be influenced by a combination of parameters. In this study, we describe the use of an online pressure measurement tool which allows to characterize pressure profiles during an extrusion run. We systematically investigated the impact of various process parameters on implant properties as well as release patterns using a monoclonal antibody (mAb). Solid lipid implants (SLIs) were produced by tsc-extrusion using the low melting triglyceride H12 and the high melting triglyceride Dynasan® D118. A mAb available in a freeze-dried matrix containing hydroxypropyl-ß-cyclodextrine (HP-ß-CD) was used as incorporated active pharmaceutical ingredient. Extrusion temperature (33-37⯰C), screw speed (40-80â¯rpm) and the lipid composition (30-70% of each triglyceride) were modified. Additionally, freshly extruded SLIs were ground and extruded again as a preparation technique to optimize properties of SLIs. Using the pressure monitoring tool, four characteristic phases were defined for an extrusion run. We found that both, sufficient pressure and adequately molten material, is needed to form a suitable implant. Using the double extrusion technique, release rates could substantially be slowed down without changing formulation.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Sistemas de Liberación de Medicamentos , Lípidos/química , Tecnología Farmacéutica/métodos , 2-Hidroxipropil-beta-Ciclodextrina/química , Química Farmacéutica/métodos , Preparaciones de Acción Retardada , Implantes de Medicamentos , Liberación de Fármacos , Proteínas/administración & dosificación , Temperatura , Triglicéridos/químicaRESUMEN
The taste of pharmaceuticals is of particular importance as it highly affects the compliance of patients, especially for patient groups like children. In view of oral solid dosage forms, various taste masking techniques can be applied encapsulating the active pharmaceutical ingredient (API) to prevent the interaction with the taste buds. Despite a delayed drug release in saliva, an immediate drug release in gastrointestinal media is desirable for efficient drug absorption. This combinatory approach is of particular interest for poorly soluble drugs still demonstrating an aversive, bitter taste, e.g. praziquantel (PZQ). It is an anthelmintic drug of current importance for adults and children as it is the recommended therapy against schistosomiasis. First, a small scale screen was conducted to identify the most suitable polymer for a combinatorial approach of taste masking and immediate release for PZQ. Among various PZQ-polymer combinations Eudragit® E PO was chosen. Second, multiparticulate systems utilizing extrusion and spray-drying were generated comprising PZQ, Eudragit® E PO and a lipid as an additional taste masking agent. Spray-dried powders and ground extrudates showed as expected strong differences in terms of particle size distribution and morphological characteristics of the encapsulated PZQ. DSC and XRPD studies revealed the formation of an amorphous solid dispersion of PZQ after spray-drying in contrast to ground extrudates. This could be correlated to drug release studies. All formulations were subjected to non-sink dissolution studies in simulated salivary (SSF), gastric (spSGF) and intestinal (FaSSIF) media. Ground extrudates provided an efficient delayed release in SSF and immediate release and supersaturation in spSGF and FaSSIF for PZQ. Spray-dried powders revealed fast solubility kinetics and up to 5-fold supersaturation in biorelevant media, contrary to a taste masking effect. Moreover, XRPD-patterns of spray-dried powders after storage detected recrystallized PZQ resulting in varied dissolution profiles. Solid lipid extrusion combined with Eudragit® E PO enabled a promising taste masking of PZQ in SSF through encapsulation of the crystalline PZQ and further, a fast and reproducible dissolution in simulated gastric and intestinal media.
Asunto(s)
Ácidos Polimetacrílicos/química , Praziquantel/química , Gusto , Antihelmínticos/química , Química Farmacéutica , Composición de Medicamentos , Liberación de Fármacos , Estabilidad de Medicamentos , Jugo Gástrico/química , Glicéridos/química , Secreciones Intestinales/química , Saliva/química , SolubilidadRESUMEN
The aim of the present study was to evaluate the solid state characteristics, drug release and stability of fatty acid-based formulations after processing via prilling and solid lipid extrusion. Myristic acid (MA), stearic acid (SA) and behenic acid (BA) were used as matrix formers combined with metoprolol tartrate (MPT) as model drug. The prilling process allowed complete dissolution of MPT in the molten fatty acid phase, generating semi-crystalline MPT and the formation of hydrogen bonds between drug and fatty acids in the solid prills. In contrast, as solid lipid extrusion (SLE) induced only limited melting of the fatty acids, molecular interaction with the drug was inhibited, yielding crystalline MPT. Although the addition of a low melting fatty acid allowed more MPT/fatty acid interaction during extrusion, crystalline MPT was detected after processing. Mathematical modeling revealed that the extrudates exhibited a higher apparent drug/water mobility than prills of the same composition, probably due to differences in the inner systems' structure. Irrespective of the processing method, mixed fatty acid systems (e.g. MA/BA) exhibited a lower matrix porosity, resulting in a slower drug release rate. Solid state analysis of these systems indicated that the crystalline structure of the fatty acids was maintained after SLE, while prilling generated a reduced MA crystallinity. Binary MPT/fatty acid systems processed via extrusion showed better stability during storage at 40 °C than the corresponding prills. Although mixed fatty acid systems were stable at 25 °C, stability problems were encountered during storage at 40 °C: a faster release was obtained from the prills, whereas drug release from the extrudates was slower.
Asunto(s)
Química Farmacéutica/métodos , Excipientes/química , Ácidos Grasos/química , Metoprolol/administración & dosificación , Cristalización , Preparaciones de Acción Retardada , Liberación de Fármacos , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Lípidos/química , Metoprolol/química , Modelos Teóricos , Ácido Mirístico/química , Porosidad , Solubilidad , Ácidos Esteáricos/química , TemperaturaRESUMEN
Solid lipids are non-toxic excipients, which are known to potentially enhance delivery and bioavailability of poorly water-soluble drugs and moreover to mask unpleasant tasting drugs. Multiple unit matrix dosage forms based on solid lipids, such as lipid pellets, can be obtained by solvent-free cold extrusion and spheronization. This method presents advantages in the processing of sensitive substances, such as low process temperatures, the absence of solvents and a drying step. However, the material temperature during the spheronization showed to be critical so far. The process leads to increased material temperatures, causing particle agglomeration and discontinuity of the spheronization. In the present study, extrudates of 0.5mm in diameter containing metformin hydrochloride, and either semisynthetic hard fat (Witocan® 42/44) or different ternary mixtures based on hard fat, glyceryl trimyristate, and glyceryl distearate, were spheronized. By applying common process parameters, particle agglomeration or material stickiness on equipment walls was observed in preliminary experiments after 2-6min, depending on the lipid composition. Therefore, an innovative instrumental setup to control the spheronization process was developed utilizing an infrared light source, which was positioned over the particle bed. The new approach enabled a spheronization process that reached the desired spheronization temperature after 2-3min and neither particle agglomeration nor material adherence occurred even after longer process times. The different formulations, even those based on high amount of solid lipids, were successfully spheronized over 15min, resulting in small diameter lipid pellets with smooth surface and aspect ratios below 1.3.
Asunto(s)
Química Farmacéutica/métodos , Excipientes/química , Lípidos/química , Metformina/administración & dosificación , Composición de Medicamentos/métodos , Sistemas de Liberación de Medicamentos , Metformina/química , Solubilidad , Solventes/química , Temperatura , Factores de TiempoRESUMEN
The overactive bladder (OAB) is a common disease with an overactivity of the detrusor muscle in the bladder wall. Besides peroral administration of anticholinergic drugs and bladder irrigations, there is a need for a sustained release formulation in the urinary bladder. In order to realise a local long-term treatment of the overactive urinary bladder, lipidic drug delivery systems were prepared. Requirements for an intravesical application are a long-term controlled release of trospium chloride, a high drug loading and small sized drug carriers to permit an insertion through the urethra into the urinary bladder. The drug delivery systems were manufactured by using compression (mini-tablets), solid lipid extrusion (extrudates) and a melting and casting technique (mini-moulds) with different amounts of trospium chloride and glyceryl tristearate as matrix former. Drug release depended on the drug loading and the preparation method. Mini-tablets and lipidic extrudates showed a drug release over five days, whereas that from mini-moulds was negligibly small. The appearance of polymorphic transformations during processing and storage was investigated by using differential scanning calorimetry and X-ray diffraction. In contrast to mini-tablets and mini-moulds, lipidic extrudates showed no polymorphic transformations. In summary, lipids are suitable matrix formers for a highly water-soluble drug, like trospium chloride. Despite a drug loading of up to 30%, it was feasible to achieve a drug release ranging from several days up to weeks. In addition, small dosage forms with a size of only a few millimetres were realised. Therefore, an insertion and excretion through the urethra is possible and the requirements for an intravesical application are fulfilled.
Asunto(s)
Bencilatos/química , Sistemas de Liberación de Medicamentos , Nortropanos/química , Agentes Urológicos/química , Rastreo Diferencial de Calorimetría , Preparaciones de Acción Retardada/química , Difracción de Polvo , Solubilidad , Estearatos/química , Comprimidos , Vejiga Urinaria , Difracción de Rayos XRESUMEN
Matrix dosage forms are widely used for sustained drug release. As both the distribution of the matrix components and physical changes during dissolution can impact drug release behavior, a comprehensive investigation of these phenomena is required during matrix development. In this study, Raman microscopy was used to investigate different extrudate formulations in terms of component distribution and structural changes during dissolution testing. Two systems containing the model drug theophylline anhydrate were investigated: a binary system, based on a tripalmitin matrix, and a ternary system, containing tripalmitin and polyethylene glycol. The distribution of the drug and the soluble and insoluble matrix components were mapped during dissolution testing. Although a receding drug boundary was observed, it was not uniformly distant from the matrix edge. The lipid structure remained intact, whereas the water-soluble polymer rapidly dissolved and diffused from the matrix leaving a more extensive network of channels through which the dissolution medium could penetrate and the drug could diffuse. Raman mapping can be considered a useful aid in the direct analysis of multiple matrix components during drug release, and therefore a deeper understanding of factors affecting drug release can be obtained during the development of sustained-release matrices.