Robustness of Controlled Release Tablets Based on a Cross-linked Pregelatinized Potato Starch Matrix.

The aim of this study was to evaluate the potential of a cross-linked pregelatinized potato starch (PREGEFLO® PI10) as matrix former for controlled release tablets. Different types of tablets loaded with diprophylline, diltiazem HCl or theophylline were prepared by direct compression of binary drug/polymer blends. The drug content was varied from 20 to 50%. Two hydroxypropyl methylcellulose grades (HPMC K100LV and K100M) were studied as alternative matrix formers. Drug release was measured in a variety of release media using different types of experimental set-ups. This includes 0.1 N HCl, phosphate buffer pH 6.8 and water, optionally containing different amounts of NaCl, sucrose, ethanol or pancreatin, fasted state simulated gastric fluid, fed state simulated gastric fluid, fasted state simulated intestinal fluid, fed state simulated intestinal fluid as well as media simulating the conditions in the colon of healthy subjects and patients suffering from Crohn's disease. The USP apparatuses I/II/III were used under a range of operating conditions and optionally coupled with the simulation of additional mechanical stress. Importantly, the drug release kinetics was not substantially affected by the investigated environmental conditions from tablets based on the cross-linked pregelatinized potato starch, similar to HPMC tablets. However, in contrast to the latter, the starch-based tablets roughly kept their shape upon exposure to the release media (they "only" increased in size) during the observation period, and the water penetration into the systems was much less pronounced. Thus, the investigated cross-linked pregelatinized potato starch offers an interesting potential as matrix former in controlled release tablets.

Development and evaluation of chitosan and chitosan derivative nanoparticles containing insulin for oral administration.

Chitosan and chitosan derivative-based nanoparticles loaded with insulin were prepared by self-assembly, via electrostatic interactions between the negatively charged drug and the positively charged polymers. In the investigated chitosan derivatives, the amine groups were substituted to different extents (33, 52 or 99%) by 2-hydroxypropyl-3-trimethyl ammonium groups, rendering the polymers permanently positively charged, irrespective of the pH. This is an important property for this type of advanced drug delivery system, since the pH value changes throughout the gastrointestinal tract and electrostatic interactions are of crucial importance for the stability of the nanoparticles. Permanent positive charges are also in favor of mucoadhesion. In contrast, the electric charges of chitosan molecules depend on the pH of the surrounding medium. Since the solubility of the chitosan derivatives increased due to the introduction of quaternary ammonium groups, sodium tripolyphosphate (TPP) was added to the systems to create supplementary cross-links and stabilize the nanoparticles. The presence of TPP influenced both the dissolution of the polymer matrix as well as the resulting release kinetics. The underlying drug release mechanisms were found to be more complex than simple diffusion under constant conditions, likely involving also ionic interactions and matrix dissolution. The most promising formulation was based on a chitosan derivative with 33% substitution degree and characterized by a Z-average of 142 ± 10 nm, a zeta potential of 29 ± 1 mV, an encapsulation efficacy of 52 ± 3% and, most importantly, the release of insulin was sustained for more than 210 min.

Mechanisms controlling theophylline release from ethanol-resistant coated pellets.

PURPOSE: To elucidate the mass transport mechanisms controlling drug release from recently proposed, ethanol-resistant, polymeric film coatings. METHODS: Theophylline matrix pellets were coated with ethylcellulose: guar gum blends. Drug release from single pellets and ensembles of pellets was measured in various release media. Changes in the systems' morphology, composition and mechanical properties were monitored using SEM, gravimetrical analysis and a texture analyzer. Based on the obtained experimental results a mechanistically realistic mathematical model was identified and used to quantitatively predict drug release from coated pellets in ethanol-free and ethanol-containing bulk fluids. RESULTS: Drug diffusion though the intact polymeric film coatings is likely to be the dominant mass transport mechanism in the investigated systems, irrespective of the ethanol content in the surrounding environment. An appropriate solution of Fick's law could be used to quantitatively predict theophylline release from pellets coated with different ethylcellulose:guar gum blends at different coating levels. Importantly, independent experiments confirmed the theoretical predictions. CONCLUSIONS: In silico simulations can help facilitating the optimization of the novel ethanol-resistant polymeric film coatings, avoiding time-consuming and cost-intensive series of trial-and-error experiments. The presence/absence of ethanol does not affect the underlying drug release mechanisms.

Colon targeting in rats, dogs and IBD patients with species-independent film coatings.

Polysaccharides were identified, which allow for colon targeting in human Inflammatory Bowel Disease (IBD) patients, as well as in rats and dogs (which are frequently used as animals in preclinical studies). The polysaccharides are degraded by colonic enzymes (secreted by bacteria), triggering the onset of drug release at the target site. It has to be pointed out that the microbiota in rats, dogs and humans substantially differ. Thus, the performance of this type of colon targeting system observed in animals might not be predictive for patients. The aim of this study was to limit this risk. Different polysaccharides were exposed to culture medium inoculated with fecal samples from IBD patients, healthy dogs and "IBD rats" (in which colonic inflammation was induced). Dynamic changes in the pH of the culture medium were used as an indicator for the proliferation of the bacteria and, thus, the potential of the polysaccharides to serve as their substrate. Fundamental differences were observed with respect to the extent of the pH variations as well as their species-dependency. The most promising polysaccharides were used to prepare polymeric film coatings surrounding 5-aminosaliciylic acid (5-ASA)-loaded starter cores. To limit premature polysaccharide dissolution/swelling in the upper gastro intestinal tract, ethylcellulose was also included in the film coatings. Drug release was monitored upon exposure to culture medium inoculated with fecal samples from IBD patients, healthy dogs and "IBD rats". For reasons of comparison, also 5-ASA release in pure culture medium was measured. Most film coatings showed highly species-dependent drug release kinetics or limited colon targeting capacity. Interestingly, extracts from aloe vera and reishi (a mushroom) showed a promising potential for colon targeting in all species.

In-situ forming PLGA implants: Towards less toxic solvents.

In-situ forming poly(lactic-co-glycolic acid) (PLGA) implants offer a great potential for controlled drug delivery for a variety of applications, e.g. periodontitis treatment. The polymer is dissolved in a water-miscible solvent. The drug is dissolved or dispersed in this solution. Upon contact with aqueous body fluids, the solvent diffuses into the surrounding tissue and water penetrates into the formulation. Consequently, PLGA precipitates, trapping the drug. Often, N-methyl-2-pyrrolidine (NMP) is used as a water-miscible solvent. However, parenteral administration of NMP raises toxicity concerns. The aim of this study was to identify less toxic alternative solvent systems for in-situ forming PLGA implants. Various blends of polyethylene glycol 400 (PEG 400), triethyl citrate (TEC) and ethanol were used to prepare liquid formulations containing PLGA, ibuprofen (as an anti-inflammatory drug) and/or chlorhexidine dihydrochloride (as an antiseptic agent). Implant formation and drug release kinetics were monitored upon exposure to phosphate buffer pH 6.8 at 37 °C. Furthermore, the syringeability of the liquids, antimicrobial activity of the implants, and dynamic changes in the latter's wet mass and pH of the release medium were studied. Importantly, 85:10:5 and 60:30:10 PEG 400:TEC:ethanol blends provided good syringeability and allowed for rapid implant formation. The latter controlled ibuprofen and chlorhexidine release over several weeks and assured efficient antimicrobial activity. Interestingly, fundamental differences were observed concerning the underlying release mechanisms of the two drugs: Ibuprofen was dissolved in the solvent mixtures and partially leached out together with the solvents during implant formation, resulting in relatively pronounced burst effects. In contrast, chlorhexidine dihydrochloride was dispersed in the liquids in the form of tiny particles, which were effectively trapped by precipitating PLGA during implant formation, leading to initial lag-phases for drug release.

3D printed PLGA implants: APF DDM vs. FDM.

3D Printing offers a considerable potential for personalized medicines. This is especially true for customized biodegradable implants, matching the specific needs of each patient. Poly(lactic-co-glycolic acid) (PLGA) is frequently used as matrix former in biodegradable implants. However, yet relatively little is known on the technologies, which can be used for the 3D printing of PLGA implants. The aim of this study was to compare: (i) Arburg Plastic Freeforming Droplet Deposition Modeling (APF DDM), and (ii) Fused Deposition Modeling (FDM) to print mesh-shaped, ibuprofen-loaded PLGA implants. During APF DDM, individual drug-polymer droplets are deposited, fusing together to form filaments, which build up the implants. During FDM, continuous drug-polymer filaments are deposited to form the meshes. The implants were thoroughly characterized before and after exposure to phosphate buffer pH 7.4 using optical and scanning electron microscopy, GPC, DSC, drug release measurements and monitoring dynamic changes in the systems' dry & wet mass and pH of the bulk fluid. Interestingly, the mesh structures were significantly different, although the device design (composition & theoretical geometry) were the same. This could be explained by the fact that the deposition of individual droplets during APF DDM led to curved and rather thick filaments, resulting in a much lower mesh porosity. In contrast, FDM printing generated straight and thinner filaments: The open spaces between them were much larger and allowed convective mass transport during drug release. Consequently, most of the drug was already released after 4 d, when substantial PLGA set on. In the case of APF DDM printed implants, most of the drug was still entrapped at that time point and substantial polymer swelling transformed the meshes into more or less continuous PLGA gels. Hence, the diffusion pathways became much longer and ibuprofen release was controlled over 2 weeks.

3D printed PLGA implants: How the filling density affects drug release.

Different types of ibuprofen-loaded, poly (D,L lactic-co-glycolic acid) (PLGA)-based implants were prepared by 3D printing (Droplet Deposition Modeling). The theoretical filling density of the mesh-shaped implants was varied from 10 to 100%. Drug release was measured in agarose gels and in well agitated phosphate buffer pH 7.4. The key properties of the implants (and dynamic changes thereof upon exposure to the release media) were monitored using gravimetric measurements, optical microscopy, Differential Scanning Calorimetry, Gel Permeation Chromatography, and Scanning Electron Microscopy. Interestingly, drug release was similar for implants with 10 and 30% filling density, irrespective of the experimental set-up. In contrast, implants with 100% filling density showed slower release kinetics, and the shape of the release curve was altered in agarose gels. These observations could be explained by the existence (or absence) of a continuous aqueous phase between the polymeric filaments and the "orchestrating role" of substantial system swelling for the control of drug release. At lower filling densities, it is sufficient for the drug to be released from a single filament. In contrast, at high filling densities, the ensemble of filaments acts as a much larger (more or less homogeneous) polymeric matrix, and the average diffusion pathway to be overcome by the drug is much longer. Agarose gel (mimicking living tissue) hinders substantial PLGA swelling and delays the onset of the final rapid drug release phase. This improved mechanistic understanding of the control of drug release from PLGA-based 3D printed implants can help to facilitate the optimization of this type of advanced drug delivery systems.

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.

Exploration of the physical states of riboflavin (free base) by mechanical milling.

Amorphous riboflavin (free base) could be produced for the first time via high energy ball milling of a commercial crystalline form (Form I). Importantly, this solid state amorphization process allowed to circumvent chemical degradation occurring during melting as well as the lack of suitable solvents, which are required for amorphization via spray- or freeze-drying. The amorphous state of riboflavin was thoroughly characterized, revealing a complex recrystallization pattern upon heating, involving two enantiotropic polymorphic forms (II and III) and a dihydrate. The glass transition temperature (Tg) and heat capacity (Cp) jump of the amorphous form were determined as 144 °C and 0.68 J/g/°C. Moreover, the relative physical stability of the different physical states has been elucidated, e.g., at room temperature: I > II > III. The following rank order was observed for the dissolution rates in water at 37 °C during the first 4 h: amorphous > III ≈ II > I. Afterwards, a dihydrate crystallized from the solutions of amorphous and metastable crystalline riboflavin forms, the solubility of which was well above the solubility of the stable FormI.

Drug release from PLGA microparticles can be slowed down by a surrounding hydrogel.

This study aimed to evaluate and better understand the potential impact that a layer of surrounding hydrogel (mimicking living tissue) can have on the drug release from PLGA microparticles. Ibuprofen-loaded microparticles were prepared with an emulsion solvent extraction/evaporation method. The drug loading was about 48%. The surface of the microparticles appeared initially smooth and non-porous. In contrast, the internal microstructure of the particles exhibited a continuous network of tiny pores. Ibuprofen release from single microparticles was measured into agarose gels and well-agitated phosphate buffer pH 7.4. Optical microscopy, scanning electron microscopy, differential scanning calorimetry, X-ray powder diffraction, and X-ray µCT imaging were used to characterize the microparticles before and after exposure to the release media. Importantly, ibuprofen release was much slower in the presence of a surrounding agarose gel, e.g., the complete release took two weeks vs. a few days in well agitated phosphate buffer. This can probably be attributed to the fact that the hydrogel sterically hinders substantial system swelling and, thus, slows down the related increase in drug mobility. In addition, in this particular case, the convective flow in agitated bulk fluid likely damages the thin PLGA layer at the microparticles' surface, giving the outer aqueous phase more rapid access to the inner continuous pore network: Upon contact with water, the drug dissolves and rapidly diffuses out through a continuous network of water-filled channels. Without direct surface access, most of the drug "has to wait" for the onset of substantial system swelling to be released.

How agarose gels surrounding PLGA implants limit swelling and slow down drug release.

The aim of this study was to better understand to which extent and in which way the presence of an agarose gel (mimicking living tissue) around a PLGA [poly(lactic-co-glycolic acid)] implant affects the resulting drug release kinetics. Ibuprofen-loaded implants were prepared by hot melt extrusion. Drug release was measured upon exposure to phosphate buffer pH 7.4 in Eppendorf tubes, as well as upon inclusion into an agarose gel which was exposed to phosphate buffer pH 7.4 in an Eppendorf tube or in a transwell plate. Dynamic changes in the implants' dry & wet mass and dimensions were monitored gravimetrically and by optical macroscopy. Implant erosion and polymer degradation were observed by SEM and GPC. Different pH indicators were used to measure pH changes in the bulk fluids, gels and within the implants during drug release. Ibuprofen release was bi-phasic in all cases: A zero order release phase (~20% of the dose) was followed by a more rapid, final drug release phase. Interestingly, the presence of the hydrogel delayed the onset of the 2nd release phase. This could be attributed to the sterical hindrance of implant swelling: After a certain lag time, the degrading PLGA matrix becomes sufficiently hydrophilic and mechanically instable to allow for the penetration of substantial amounts of water into the system. This fundamentally changes the conditions for drug release: The latter becomes much more mobile and is more rapidly released. A gel surrounding the implant mechanically hinders system swelling and, thus, slows down drug release. These observations also strengthen the hypothesis of the "orchestrating" role of PLGA swelling for the control of drug release and can help developing more realistic in vitro release set-ups.

PLGA implants for controlled drug release: Impact of the diameter.

The aim of this study was to better understand the importance of the diameter of poly(lactic-co-glycolic acid) (PLGA)-based implants on system performance, in particular the control of drug release. Different types of ibuprofen-loaded implants were prepared by hot melt extrusion using a Leistritz Nano 16 twin-screw extruder. Drug release was measured in well agitated phosphate buffer pH7.4 bulk fluid and in agarose gels in Eppendorf tubes or transwell plates. Dynamic changes in the implants' dry & wet mass, volume, polymer molecular weight as well as inner & outer morphology were monitored using gravimetric analysis, optical macroscopy, gel permeation chromatography and scanning electron microscopy. The physical states of the drug and polymer were determined by DSC. Also pH changes in the release medium were investigated. Irrespective of the type of experimental set-up, the resulting absolute and relative drug release rates decreased with increasing implant diameter (0.7-2.8 mm). Bi-phasic drug release was observed in all cases from the monolithic solutions (ibuprofen was dissolved in the polymer): A zero order release phase was followed by a final, rapid drug release phase (accounting for 80-90% of the total drug dose). The decrease in the relative drug release rate with increasing system diameter can be explained by the increase in the diffusion pathway lengths to be overcome. Interestingly, also the onset of the final rapid drug release phase was delayed with increasing implant diameter. This can probably be attributed to the higher mechanical stability of thicker devices, offering more resistance to substantial entire system swelling.

How bulk fluid renewal can affect in vitro drug release from PLGA implants: Importance of the experimental set-up.

The aim of this study was to better understand the potential impact of partial vs. complete renewal of the bulk fluid during drug release measurements from poly (lactic-co-glycolic acid) (PLGA)-based implants. A "standard experimental set-up", in which the implants were directly exposed to well agitated phosphate buffer pH 7.4 was used, as well as set-ups, in which the implants were embedded within agarose hydrogels (mimicking living tissue). The gels were exposed to well agitated phosphate buffer pH 7.4. Ibuprofen-loaded implants were prepared by hot melt extrusion. The systems were thoroughly characterized before and during drug release by optical and scanning electron microscopy, gravimetric analysis, pH and solubility measurements as well as gel permeation chromatography. The bulk fluid was either completely or partially replaced by fresh medium at each sampling time point. In all cases, sink conditions were provided in the agitated bulk fluids throughout the experiments. Interestingly, the agarose set-ups did not show any noteworthy impact of the bulk fluid sampling volume on the observed drug release patterns, whereas complete fluid renewal in the "standard set-up" led to accelerated drug release. This could be explained by the considerable fragility of the implants once substantial polymer swelling set on, transforming them into PLGA gels: Complete fluid renewal caused partial disintegration and damage of the highly swollen systems, decreasing the lengths of the diffusion pathways for the drug. The mechanical stress is very much reduced at low sampling volumes, or if the implants are embedded within agarose gels. Thus, great care must be taken when defining the conditions for in vitro drug release measurements from PLGA-based implants: Once substantial system swelling sets on, the devices become highly fragile.

Long term behavior of dexamethasone-loaded cochlear implants: In vitro & in vivo.

The aim of this study was to better understand the long term behavior of silicone-based cochlear implants loaded with dexamethasone: in vitro as well as in vivo (gerbils). This type of local controlled drug delivery systems offers an interesting potential for the treatment of hearing loss. Because very long release periods are targeted (several years/decades), product optimization is highly challenging. Up to now, only little is known on the long term behavior of these systems, including their drug release patterns as well as potential swelling or shrinking upon exposure to aqueous media or living tissue. Different types of cylindrical, cochlear implants were prepared by injection molding, varying their dimensions (being suitable for use in humans or gerbils) and initial drug loading (0, 1 or 10%). Dexamethasone release was monitored in vitro upon exposure to artificial perilymph at 37 °C for >3 years. Optical microscopy, X-ray diffraction and Raman imaging were used to characterize the implants before and after exposure to the release medium in vitro, as well as after 2 years implantation in gerbils. Importantly, in all cases dexamethasone release was reliably controlled during the observation periods. Diffusional mass transport and limited drug solubility effects within the silicone matrices seem to play a major role. Initially, the dexamethasone is homogeneously distributed throughout the polymeric matrices in the form of tiny crystals. Upon exposure to aqueous media or living tissue, limited amounts of water penetrate into the implant, dissolve the drug, which subsequently diffuses out. Surface-near regions are depleted first, resulting in an increase in the apparent drug diffusivity with time. No evidence for noteworthy implant swelling or shrinkage was observed in vitro, nor in vivo. A simplified mathematical model can be used to facilitate drug product optimization, allowing the prediction of the resulting drug release rates during decades as a function of the implant's design.

Non-coated multiparticulate matrix systems for colon targeting.

BACKGROUND: Colon specific drug delivery can significantly improve the efficacy of local treatments of inflammatory bowel diseases. Film coatings containing the starch derivative Nutriose have recently been reported to minimize 5-ASA release in media simulating the upper gastro intestinal tract (GIT), while releasing the drug in a time-controlled manner upon contact with feces from Crohn's Disease and Ulcerative Colitis patients. It was the aim of this study to prepare Nutriose-containing matrix pellets and mini tablets in order to avoid a film coating step. METHODS: Highly dosed matrix pellets were prepared by extrusion-spheronization, highly dosed mini tablets by compression. Various types of lipids were added and drug release measured in 0.1 N HCl and phosphate buffer pH 6.8, optionally containing pepsin and pancreatin. RESULTS: The type of added lipid and the preparation technique, in particular the curing conditions, significantly affected the resulting drug release kinetics. Glyceryl palmitostearate containing pellets and mini tablets showed the most promising results upon appropriate curing, minimizing premature drug release in media simulating the upper GIT. CONCLUSION: The proposed novel multiparticulates do not require a film coating step and show an interesting potential for site-specific drug delivery to the colon of inflammatory bowel disease patients.

Mechanistic explanation of the (up to) 3 release phases of PLGA microparticles: Monolithic dispersions studied at lower temperatures.

The aim of this study was to better understand the underlying drug release mechanisms in poly(lactic-co-glycolic acid) (PLGA) microparticles in which the drug is dispersed in the form of tiny particles ("monolithic dispersions"). Differently sized diprophylline-loaded microparticles were prepared using a solid-in-oil-in-water solvent extraction/evaporation technique. The microparticles were characterized before and after exposure to phosphate buffer pH 7.4 at 4, 20 and 37 °C. In vitro drug release was measured from ensembles and single microparticles. GPC, DSC, SEM, gravimetric analysis, drug solubility measurements and optical microscopy were used to elucidate the importance of polymer swelling & degradation, drug dissolution and diffusion. The diprophylline was initially homogeneously distributed throughout the microparticles in the form of tiny crystals. The burst release (1st phase) was strongly temperature-dependent and likely attributable to the dissolution of drug crystals with direct surface access (potentially via tiny pores). The about constant release rate during the 2nd phase also strongly depended on the temperature. It can probably be explained by the dissolution of drug crystals in surface near regions undergoing local swelling. During the observation period, the 3rd (again rapid) drug release phase was only observed at 37 °C, and seems to be caused by substantial PLGA swelling throughout the entire microparticles. This phase starts as soon as a critical polymer molecular weight of about 25 kDa is reached: Significant amounts of water penetrate into the systems, dissolving the remaining diprophylline crystals and substantially increasing the mobility of the dissolved drug molecules. Thus, this study provides additional experimental evidence (obtained at lower temperatures) confirming the hypothesized root causes for drug release from PLGA microparticles containing dispersed drug particles.

Dexamethasone-loaded cochlear implants: How to provide a desired "burst release".

Cochlear implants containing iridium platinum electrodes are used to transmit electrical signals into the inner ear of patients suffering from severe or profound deafness without valuable benefit from conventional hearing aids. However, their placement is invasive and can cause trauma as well as local inflammation, harming remaining hair cells or other inner ear cells. As foreign bodies, the implants also induce fibrosis, resulting in a less efficient conduction of the electrical signals and, thus, potentially decreased system performance. To overcome these obstacles, dexamethasone has recently been embedded in this type of implants: into the silicone matrices separating the metal electrodes (to avoid short circuits). It has been shown that the resulting drug release can be controlled over several years. Importantly, the dexamethasone does not only act against the immediate consequences of trauma, inflammation and fibrosis, it can also be expected to be beneficial for remaining hair cells in the long term. However, the reported amounts of drug released at "early" time points (during the first days/weeks) are relatively low and the in vivo efficacy in animal models was reported to be non-optimal. The aim of this study was to increase the initial "burst release" from the implants, adding a freely water-soluble salt of a phosphate ester of dexamethasone. The idea was to facilitate water penetration into the highly hydrophobic system and, thus, to promote drug dissolution and diffusion. This approach was efficient: Adding up to 10% dexamethasone sodium phosphate to the silicone matrices substantially increased the resulting drug release rate at early time points. This can be expected to improve drug action and implant functionality. But at elevated dexamethasone sodium phosphate loadings device swelling became important. Since the cochlea is a tiny and sensitive organ, a potential increase in implant dimensions over time must be limited. Hence, a balance has to be found between drug release and implant swelling.

Sink conditions do not guarantee the absence of saturation effects.

Limited drug solubility effects can play a major role for the control of drug release from a variety of drug delivery systems, e.g. tablets, pellets, implants and microparticles. Importantly, such saturation effects can occur inside and/or outside the dosage form. This is true for drug release occurring in vitro and in vivo. In vivo, released drug might be rapidly transported away from the site of administration, e.g. due to absorption into the blood stream. In vitro, many frequently used experimental set-ups are "closed systems" and eventually drug saturation effects in the surrounding release medium might artificially occur, "falsifying" the resulting release kinetics. To avoid such errors, often "sink conditions" are provided: Selecting appropriate release medium volumes, renewal rates and/or "open systems", it is assured that the maximum concentration in the release medium does not exceed about 20% of the drug solubility. However, this does not mean that drug saturation effects within the dosage form are also avoided. It should clearly be distinguished between potential limited drug solubility effects inside versus outside the drug delivery system. This articles aims at: (i) giving a brief overview on the underlying physico-chemical phenomena involved in drug dissolution and drug release, (ii) clarifying some key terms, and (iii) presenting several examples of dosage forms in which drug saturation effects within the system are of importance, even when providing sink conditions in the surrounding bulk fluid. Interestingly, this can also include highly hydrated delivery systems containing freely water-soluble drugs.

Porous pellets as drug delivery system.

BACKGROUND: Multiparticulate drug delivery systems, such as pellets, are frequently used as they offer therapeutic advantages over single-unit dosage forms. AIM: Development of porous pellets followed by evaluation of potential drug loading techniques. METHOD: Porous microcrystalline pellets were manufactured and evaluated as drug delivery system. Pellets consisting of Avicel PH 101 and NaCl (70%, w/w) were prepared by extrusion/spheronization. The NaCl fraction was extracted with water and after drying porous pellets were obtained (33.2% porosity). Immersion of the porous pellets in a 15% and 30% (w/v) metoprolol tartrate solution, ibuprofen impregnation via supercritical fluids and paracetamol layering via fluidized bed coating were evaluated as drug loading techniques. RESULTS: Raman spectroscopy revealed that immersion of the pellets in a drug solution and supercritical fluid impregnation allowed the drug to penetrate into the porous structure of the pellets. The amount of drug incorporated depended on the solubility of the drug in the solvent (water or supercritical CO(2)). Drug release from the porous pellets was immediate and primarily controlled by pure diffusion. CONCLUSION: The technique described in this research work is suitable for the production of porous pellets. Drug loading via immersion the pellets in a drug solution and supercritical fluid impregnation resulted in a drug deposition in the entire pellet in contrast to fluid bed layering where drugs were only deposed on the pellet surface.

Coloring of PLGA implants to better understand the underlying drug release mechanisms.

Different dyes and a colored vitamin (riboflavin) were used to better understand the underlying drug release mechanisms in poly(lactic-co-glycolic acid) (PLGA)-based implants. The latter were prepared by hot melt extrusion (HME) or formed in-situ, upon solvent exchange when injecting a PLGA solution in N-methyl-pyrrolidone (NMP) into phosphate buffer pH 7.4. Methylene blue was used as water-soluble dye to stain the release medium, riboflavin as a yellow, water-soluble "model drug", and Sudan-III-red as poorly water-soluble dye, incorporated in the implant. In the case of pre-formed HME implants, the "orchestrating" role of polymer swelling for the control of drug release could be visualized: At early time points, only limited amounts of water penetrate into the system, insufficient for noteworthy drug dissolution and diffusion. However, bulk erosion starts, and once a critical polymer molecular weight threshold value is reached, substantial implant swelling sets on: Large amounts of water come in and allow for significant drug dissolution and diffusion. In the case of in-situ forming implants, the importance of the composition of the liquid formulation for the resulting inner implant structure could be visualized. The latter affects the rate and extent at which water penetrates into the system and, thus, the resulting drug release rate.