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International audience; A variety of polymer:polymer blends was used to prepare hot melt extrudates and empty capsules (bodies and caps) by injection-molding using a benchtop extruder (Babyplast). Kollidon SR:inulin and Carbothane:inulin blends were investigated. The impact of the blend ratio on the water uptake and dry mass loss kinetics upon exposure to 0.1 M HCl, phosphate buffer pH 6.8 and culture medium optionally inoculated with fecal samples from Inflammatory Bowel Disease (IBD) patients were studied. Hot melt extrudates were loaded with up to 60 % theophylline, capsules were filled with drug powder. Increasing the inulin content led to increased water uptake and dry mass loss rates, resulting in accelerated drug release from the dosage forms, irrespective of the type of polymer blend. This can be attributed to the higher hydrophilicity/water-solubility of this polymer compared to Kollidon SR and Carbothane. Interestingly, the presence of fecal samples in culture medium increased the water uptake and dry mass loss of hot melt extrudates to a certain extent, suggesting partial system degradation by bacterial enzymes. However, these phenomena did not translate into any noteworthy impact of the presence of colonic bacteria on theophylline release from the investigated extrudates or capsules. Hence, drug release can be expected to be independent of the location “small intestine vs. colon” from these dosage forms, which can be advantageous for long term release throughout the entire gastro intestinal tract.

International audience; A variety of poly(ethylene oxide) (PEO)-based matrix tablets loaded with theophylline, ibuprofen or metoprolol tartrate was prepared via hot melt extrusion. The initial drug loading was varied from 10 to 60 %, the PEO polymer molecular weight from 300 to 7,000 kDa. The extrudates were characterized before and after exposure to phosphate buffer pH 7.4 at 37 °C using optical and scanning electron microscopy, X-ray diffraction analysis and drug release measurements. In the case of metoprolol tartrate, the resulting drug release rates monotonically increased with increasing initial drug loading, irrespective of the PEO grade. This can be attributed to an “increased porosity effect” upon drug leaching, resulting in less hindrance for subsequent drug release. However, in the case of theophylline and ibuprofen, also “limited drug solubility effects” played a role and were even dominant in 7,000 kDa PEO-based extrudates: Upon water penetration into the system, not all of the drug was dissolved. Dissolved and non-dissolved drug co-existed. Importantly, only dissolved drug is available for diffusion. Thus, increasing the initial drug content did not increase the concentration gradients of dissolved drug (and the absolute drug release rates in the absence of porosity effects), but increased the 100 % reference values. Interestingly, in 300 kDa PEO-based extrudates, “increased porosity effects” dominated for all drugs, and the relative release rates always increased with increasing drug loading. At 1,000 and 7,000 kDa, the resulting released rate increased or decreased with increasing drug loading, depending of the type of drug.

International audience; The aim of this study was to gain deeper insight into the mass transport mechanisms controlling drug release from polymer-coated pellets using non-invasive analytical tools. Pellet starter cores loaded with verapamil HCl (10% loading, 45% lactose, 45% microcrystalline ellulose) were prepared by extrusion/spheronization and coated with 5% Kollicoat SR:IR 95:5 or 10% Kollicoat SR:IR 90:10. Drug release was measured from ensembles of pellets as well as from single pellets upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4. The swelling of single pellets was observed by optical microscopy, while dynamic changes in the pH in the pellet cores were monitored by fluorescence spectroscopy. Also, mathematical modeling using a mechanistically realistic theory as well as SEM and Raman imaging were applied to elucidate whether drug release mainly occurs by diffusion through the intact film coatings or whether crack formation in the film coatings plays a role. Interestingly, fluorescence spectroscopy revealed that the pH within the pellet cores substantially differed upon exposure to acetate buffer pH = 3.5 and phosphate buffer pH = 7.4, resulting in significant differences in drug solubility (verapamil being a weak base) and faster drugrelease at lower pH: from ensembles of pellets and single pellets. The monitoring of drug release from and the swelling of single pellets indicated that crack formation in the film coatings likely plays a major role, irrespective of the Kollicoat SR:IR ratio/coating level. This was confirmed by mathematical modeling, SEM and Raman imaging. Importantly, the latter technique allowed also for non-invasive measurements, reducing the risk of artifact creation associated with sample cutting with a scalpel.

Different types of in-situ forming implants based on poly(lactic-co-glycolic acid) (PLGA) and N-methyl-pyrrolidone (NMP) were prepared for controlled ocular delivery of dexamethasone. The impact of the volume of the release medium, initial drug content, polymer molecular weight and PLGA concentration on the resulting drug release kinetics were studied and explained based on a thorough physico-chemical characterization of the systems. This included for instance the monitoring of dynamic changes in the implants' wet and dry mass, morphology, PLGA polymer molecular weight, pH of the surrounding bulk fluid and water/NMP contents upon exposure to phosphate buffer pH 7.4. Importantly, the systems can be expected to be rather robust with respect to variations in the vitreous humor volumes encountered in vivo. Interestingly, limited drug solubility effects within the implants as well as in the surrounding aqueous medium play an important role for the control of drug release at a drug loading of only 7.5%. Furthermore, the polymer molecular weight and PLGA concentration in the liquid formulations are decisive for how the polymer precipitates during solvent exchange and for the swelling behavior of the systems. These features determine the resulting inner system structure and the conditions for mass transport. Consequently, they affect the degradation and drug release of the in-situ formed implants.

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.

Dexamethasone-loaded, poly(lactic- co -glycolic acid) (PLGA) microparticles were prepared using an oil-in-water solvent extraction/evaporation method. The drug loading was varied from 2.4 to 61.9%, keeping the mean particle size in the range of 52–61 μm. In vitro drug release was characterized by up to 3 phases: (1) an (optional) initial burst release, (2) a phase with an about constant drug release rate, and (3) a final, again rapid, drug release phase. The importance and durations of these phases strongly depended on the initial drug loading. To better understand the underlying mass transport mechanisms, the microparticles were thoroughly characterized before and after exposure to the release medium. The initial burst release seems to be mainly due to the dissolution of drug particles with direct access to the microparticles’ surface. The extent of the burst was negligible at low drug loadings, whereas it exceeded 60% at high drug loadings. The second release phase seems to be controlled by limited drug solubility effects and drug diffusion through the polymeric systems. The third drug release phase is likely to be a consequence of substantial microparticle swelling, leading to a considerable increase in the systems’ water content and, thus, fundamentally increased drug mobility.

A new type of advanced drug delivery systems is proposed: Miniaturized implants, which can be placed into tiny holes drilled into (or close to) the oval window. They consist of two parts: 1) A cylinder, which is inserted into the hole crossing the oval window. The cylinder (being longer than the depth of the hole) is partly located within the inner ear and surrounded by perilymph. This provides direct access to the target site, and at the same time assures implant fixation. 2) A cuboid, which is located in the middle ear, serving as a drug reservoir. One side of the cuboid is in direct contact with the oval window. Drug release into the cochlea occurs by diffusion through the cylindrical part of the Ear Cubes and by diffusion from the cuboid into and through the oval window. High precision molds were used to prepare two differently sized Ear Cubes by injection molding. The miniaturized implants were based on silicone and loaded with different amounts of dexamethasone (10 to 30 % w/w). The systems were thoroughly characterized before and upon exposure to artificial perilymph at 37°C. Importantly, drug release can effectively be controlled and sustained during long time periods (up to several years). Furthermore, the implants did not swell or erode to a noteworthy extent during the observation period. Drug diffusion through the polymeric matrix, together with limited dexamethasone solubility effects, seem to control the resulting drug release kinetics, which can roughly be estimated using mathematical equations derived from Fick's second law. Importantly, the proposed Ear Cubes are likely to provide much more reliable local long term drug delivery to the inner ear compared to liquid or semi-solid dosage forms administered into the middle ear, due to a more secured fixation. Furthermore, they require less invasive surgeries and can accommodate higher drug amounts compared to intracochlear implants. Thus, they offer the potential to open up new horizons for innovative therapeutic strategies to treat inner ear diseases and disorders.

International audience; Metoprolol tartrate and metoprolol free base loaded pellet starter cores were coated with Eudragit RS, plasticized with 25% triethyl citrate (TEC). The initial drug loading and coating level were varied from 10 to 40 and 0 to 20%, respectively. Drug release was measured in 0.1 N HCl and phosphate buffer pH 7.4. The water uptake and swelling kinetics, mechanical properties and TEC leaching of/from coated pellets and/or thin, free films of identical composition as the film coatings were monitored. The following unusual tendencies were observed: (i) the relative drug release rate from coated pellets increased with increasing initial drug content, and (ii) drug release from pellets was much faster for metoprolol free base compared to metoprolol tartrate, despite its much lower solubility (factor >70). These phenomena could be explained by plasticizing effects of the drug for the polymeric film coatings. In particular: 1) Metoprolol free base is a much more potent plasticizer for Eudragit RS than the tartrate, leading to higher film permeability and overcompensating the pronounced differences in drug solubility. Also, Raman imaging revealed that substantial amounts of the free base migrated into the film coatings, whereas this was not the case for the tartrate. 2) The plasticizing effects of the drug for the film coating overcompensated potential increasing limited solubility effects when increasing the initial drug loading from 10 to 40%. In summary, this study clearly demonstrates how important the plasticization of polymeric controlled release film coatings by drugs can be, leading to unexpected formulation effects.

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.

Coated pellets and mini-tablets were prepared containing a new broad spectrum antibacterial agent: CIN-102, a well-defined, synergistic blend of trans-cinnamaldehyde, trans-2-methoxycinnamaldehyde, cinnamyl acetate, linalool, β-caryophyllene, cineol and benzyl benzoate. The aim was to provide a new treatment method for colitis, especially for Inflammatory Bowel Disease (IBD) patients. Since the simple oral gavage of CIN-102 was not able to reduce the pathogenic bacteria involved in colitis (rat model), the drug was incorporated into multiparticulates. The idea was to minimize undesired drug release in the upper gastrointestinal tract and to control CIN-102 release in the colon, in order to optimize the resulting antibiotic concentration at the site of action. A particular challenge was the fact that CIN-102 is a volatile hydrophobic liquid. Pellet cores were prepared by extrusion-spheronization and coated with polymer blends, which are sensitive to colonic bacterial enzymes. Mini-tablets were prepared by direct compression. The release of the main compound of CIN-102 (cinnamaldehyde, 86.7% w/w) was monitored in vitro. Optimized coated pellets and mini-tablets were also tested in vivo: in seven-week-old, male mice suffering from dextran sodium sulfate induced colitis. Importantly, both types of multiparticulates were able: (i) to significantly reduce the number of luminal and mucosal enterobacteria in the mice (the levels of which are increased in the disease state), and (ii) to improve the clinical course of the intestinal inflammation (decrease in the percentages of mice with bloody stools and diarrhea). Thus, the proposed coated pellets and matrix mini-tablets allowing for controlled CIN-102 release show a promising potential for new treatment methods of colitis.

The aim of this study was to investigate the impact of the addition of different amounts of magnesium aluminum silicate (MAS) to polymeric films based on quaternary polymethacrylates (QPMs, here Eudragit RS and RL). MAS contains negatively charged SiO(-) groups, while QPM contains positively charged quaternary ammonium groups. The basic idea is to be able to provide desired water and drug permeability by simply varying the amount of added MAS. Thin, free films of varying composition were prepared by casting and exposed to 0.1M HCl and pH 6.8 phosphate buffer. The water uptake kinetics and water vapor permeability of the systems were determined gravimetrically. The transport of propranolol HCl, acetaminophen, methyl-, ethyl- and propylparaben across thin films was studied using side-by-side diffusion cells. A numerical solution of Fick's second law of diffusion was applied to determine the apparent compound diffusion coefficients, partition coefficients between the bulk fluids and the films as well as the apparent film permeability for these compounds. The addition of MAS resulted in denser inner film structures, at least partially due to ionic interactions between the positively charged quaternary ammonium groups and the negatively charged SiO(-) groups. This resulted in lower water uptake, reduced water vapor permeability and decreasing apparent compound diffusivities. In contrast, the affinity of the investigated drugs and parabens to the films substantially increased upon MAS addition. The obtained new knowledge can be helpful for the development of novel coating materials (based on QPM-MAS blends) for controlled-release dosage forms.

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.

Different types of ground hot-melt extrudates loaded with 10, 20 or 30 % of the poorly water-soluble drug tadalafil were prepared and characterized in vitro and in vivo (in rats). Soluplus was used as an amorphous carrier material, whereas mannitol and lactitol were studied as crystalline matrix formers. The systems were characterized using X-ray powder diffraction, thermogravimetric analysis coupled with quadruple mass spectrometry, differential scanning calorimetry, X-ray computed microtomography, in vitro drug release measurements and monitoring of drug plasma levels upon oral administration to rats. The pure drug substance and physical mixtures of tadalafil with the carrier materials were used as references. Importantly, the bioavailability of this poorly water-soluble drug could be substantially increased with the proposed formulations, and the in vitro and in vivo release rates could be effectively adjusted by choosing the appropriate type of carrier material: Whereas mannitol-based ground hot-melt extrudates rapidly released the drug and led to an early rise in drug plasma concentrations, Soluplus-based systems released tadalafil more slowly, resulting in delayed plasma peaks. These behaviors could be explained by the rapid disintegration/dissolution of the porous mannitol-based formulations, whereas Soluplus significantly swelled and the dissolved drug had to diffuse through the polymeric network prior to release. Blending these formulations can be expected to allow providing elevated drug concentrations in vivo during prolonged periods of time upon one single administration with a rapid onset of drug action.

The aim of this study was to elucidate the importance of potential limited solubility effects for the control of drug release from hydrophilic matrix tablets loaded with a freely water-soluble drug. It is often assumed that the considerable amounts of water penetrating into this type of advanced drug delivery systems are sufficient to rapidly dissolve the entire drug loading, and that limited drug solubility is not playing a role for the control of drug release. Here, we show that this assumption can be erroneous. HPMC/lactose matrix tablets were loaded with 5 to 60% diprophylline (e.g. solubility in 0.1M HCl at 37°C: 235mg/mL), and drug release was measured at low and neutral pH, respectively. A mechanistically realistic mathematical theory was applied, considering drug diffusion in axial and radial direction in the cylindrical matrices and the potential co-existence of dissolved and non-dissolved drug. Importantly, only dissolved drug is available for diffusion. It is demonstrated that during major parts of the release periods, non-dissolved drug excess exists within tablets containing 30% or more diprophylline, despite of the substantial water contents of the systems. This leads to partially almost linear drug concentration distance profiles within the tablets, and reveals a major contribution of limited drug solubility effects to the control of drug release, even in the case of freely water-soluble diprophylline. It can be expected that also in other types of drug delivery systems, e.g. microparticles and implants (containing much less water), limited drug solubility effects play a much more important role than currently recognized.

A mechanistically realistic mathematical model is presented allowing for the quantification of niacin release from lipid tablets, based on glyceryl dibehenate. The systems were prepared either by direct compression or via hot-melt extrusion/grinding/compression. The model assumptions are based on a thorough physico-chemical characterization of the tablets before and after exposure to the release medium. Importantly, the model allows for the first time for the quantitative prediction of the effects of the composition, dimensions and type of preparation method of the tablets on the resulting niacin release kinetics. These quantitative theoretical model predictions were confirmed by several sets of independent experimental results. Furthermore, in silico simulations revealed the fundamental importance of limited niacin solubility within the lipid tablets: during major parts of the release periods, very steep concentration gradients exist and net vitamin flux is restricted to specific regions within the tablets.

Fenofibrate-loaded microparticles based on PVP/Eudragit E or HPMC/Eudragit E blends were prepared by spray-drying. The composition of the systems (in particular the polymer/polymer blend ratio and the drug loading) was varied and the resulting key properties were determined (including drug release measurements in 0.1 M HCl, X-ray diffraction studies, solubility measurements and particle size analysis). For reasons of comparison, also the respective physical drug/polymer/polymer mixtures, microparticles based on binary drug/PVP and drug/HPMC blends, the fenofibrate powder as received and a commercially available drug product were investigated. Importantly, highly supersaturated fenofibrate solutions were created upon exposure of the different types of microparticles to the release medium, in contrast to any reference formulation. Also, the presence of co-dissolved Eudragit E led to a significant increase in fenofibrate solubility. At 10 % drug loading, all microparticles were amorphous and drug release stable during one month open storage. However, at 30 % loading, HPMC containing microparticles showed storage instability, due to drug re-crystallization.

Polymeric matrices loaded with 10–50% ketoprofen were prepared by hot-melt extrusion or spray-drying. Eudragit® E, PVP, PVPVA and HPMC were studied as matrix formers. Binary “drug–Eudragit® E” as well as ternary “drug–Eudragit® E-PVP”, “drug–Eudragit® E-PVPVA” and “drug–Eudragit® E-HPMC” combinations were investigated and characterized by optical macro/microscopy, SEM, particle size measurements, mDSC, X-ray diffraction and in vitro drug release studies in 0.1 M HCl. In all cases ketoprofen release was much faster compared to a commercially available product and the dissolution of the drug powder (as received). Super-saturated solutions were obtained, which were stable during at least 2 h. Importantly, not only the composition of the systems, but also their inner structure potentially significantly affected the resulting ketoprofen release kinetics: For instance, spray-drying ternary ketoprofen:Eudragit® E:HPMC combinations led to a more homogenous HPMC distribution within the systems than hot-melt extrusion, as revealed by mDSC and X-ray diffraction. This more homogenous HPMC distribution resulted in more pronounced hindrance for water and drug diffusion and, thus, slower drug release from spray-dried powder compared to hot-melt extrudates of identical composition. This “homogeneity/heterogeneity effect” even overcompensated the “system size effect”: the surface exposed to the release medium was much larger in the case of the spray-dried powder. All formulations were stable during storage at ambient conditions in open vials.

Recently, ethylcellulose/guar gum blends have been reported to provide ethanol-resistant drug release kinetics from coated dosage forms. This is because the ethanol insoluble guar gum effectively avoids undesired ethylcellulose dissolution in ethanol-rich bulk fluids. However, so far the importance of crucial formulation parameters, including the minimum amount of guar gum to be incorporated and the minimum required guar gum viscosity, remains unclear. The aim of this study was to identify the most important film coating properties, determining whether or not the resulting drug release kinetics is ethanol-resistant. Theophylline matrix cores were coated in a fluid bed with blends of the aqueous ethylcellulose dispersion "Aquacoat®ECD30" and guar gum. The polymer blend ratio, guar gum viscosity, and degree of dilution of the final coating dispersion were varied. Importantly, it was found that more than 5% guar gum (referred to the total polymer content) must be incorporated in the film coating and that the apparent viscosity of a 1% aqueous guar gum solution must be greater than 150 cP to provide ethanol-resistance. In contrast, the investigated degree of coating dispersion dilution was not found to be decisive for the ethanol sensitivity. Furthermore, all investigated formulations were long term stable, even upon open storage under stress conditions for 6 months.

The dissolution of a drug administered in the solid state is a pre-requisite for efficient subsequent transport within the human body. This is because only dissolved drug molecules/ions/atoms are able to diffuse, e.g. through living tissue. Thus, generally major barriers, including the mucosa of the gastro intestinal tract, can only be crossed after dissolution. Consequently, the process of dissolution is of fundamental importance for the bioavailability and, hence, therapeutic efficacy of various pharmaco-treatments. Poor aqueous solubility and/or very low dissolution rates potentially lead to insufficient availability at the site of action and, hence, failure of the treatment in vivo, despite a potentially ideal chemical structure of the drug to interact with its target site. Different physical phenomena are involved in the process of drug dissolution in an aqueous body fluid, namely the wetting of the particle's surface, breakdown of solid state bonds, solvation, diffusion through the liquid unstirred boundary layer surrounding the particle as well as convection in the surrounding bulk fluid. Appropriate mathematical equations can be used to quantify these mass transport steps, and more or less complex theories can be developed to describe the resulting drug dissolution kinetics. This article gives an overview on the current state of the art of modeling drug dissolution and points out the assumptions the different theories are based on. Various practical examples are given in order to illustrate the benefits of such models. This review is not restricted to mathematical theories considering drugs exhibiting poor aqueous solubility and/or low dissolution rates, but also addresses models quantifying drug release from controlled release dosage forms, in which the process of drug dissolution plays a major role.

Novel PLGA derivatives bearing carboxylated side chains have been synthesized and used to encapsulate the fragile drug apomorphine HCl with a solid-in-oil-in-water solvent extraction/evaporation method. Blends of d,l-lactide and l-3-(2-Benzyloxycarbonyl)Ethyl-1,4-Dioxane-2,5-dione (BED) were co-polymerized at different ratios via ring-opening using benzyl alcohol as initiator. Optionally, the ester groups in the side chains as well as the terminal ester groups were hydrogenolyzed (leading to free COOH groups). For reasons of comparison, different types of "conventional" PLGAs were also synthesized and used for apomorphine HCl encapsulation. The polymers and microparticles were thoroughly characterized using SEC, (1)H NMR, DSC, SEM, X-ray and laser diffraction, Headspace-GC as well as in vitro drug release measurements in flow-through cells and agitated flasks. Importantly, microparticles based on the new polymers bearing carboxylic groups in the polymeric side chains: (i) allowed a significant reduction of the amount of residual solvent (dichloromethane), and (ii) provided different types of drug release patterns compared to microparticles based on "conventional" PLGAs (at least partially due to altered polymer degradation kinetics). Thus, they offer an interesting potential as novel matrix formers in controlled drug delivery systems, overcoming potential shortcomings of standard PLGAs.

The aim of this study was to use a mechanistically realistic mathematical model based on Fick‘s second law to quantitatively predict the release profiles from solid lipid extrudates consisting of a ternary matrix. Diprophylline was studied as a freely water-soluble model drug, glycerol tristearate as a matrix former and polyethylene glycol or crospovidone as a pore former (blend ratio: 50:45:5% w/w/w). The choice of these ratios is based on former studies. Strains with a diameter of 0.6, 1, 1.5, 2.7 and 3.5 mm were prepared using a twin-screw extruder at 65 °C and cut into cylinders of varying lengths. Drug release in demineralised water was measured using the USP 32 basket apparatus. Based on SEM pictures of extrudates before and after exposure to the release medium as well as on DSC measurements and visual observations, an analytical solution of Fick’s second law of diffusion was identified in order to quantify the resulting diprophylline release kinetics from the systems. Fitting the model to one set of experimentally determined diprophylline release kinetics from PEG containing extrudates allowed determining the apparent diffusion coefficient of this drug (or water) in this lipid matrix. Knowing this value, the impact of the dimensions of the cylinders on drug release could be quantitatively predicted. Importantly, these theoretical predictions could be confirmed by independent experimental results. Thus, diffusion is the dominant mass transport mechanism controlling drug release in this type of advanced drug delivery systems. In contrast, theoretical predictions of the impact of the device dimensions in the case of crospovidone containing extrudates significantly underestimated the real diprophylline release rates. This could be attributed to the disintegration of this type of dosage forms when exceeding a specific minimal device diameter. Thus, mathematical modelling can potentially significantly speed up the development of solid lipid extrudates, but care has to be taken that none of the assumptions the mathematical theory is based on is violated.

Fifty years ago, the legendary Professor Takeru Higuchi published the derivation of an equation that allowed for the quantification of drug release from thin ointment films, containing finely dispersed drug into a perfect sink. This became the famous Higuchi equation whose fiftieth anniversary we celebrate this year. Despite the complexity of the involved mass transport processes, Higuchi derived a very simple equation, which is easy to use. Based on a pseudo-steady-state approach, a direct proportionality between the cumulative amount of drug released and the square root of time can be demonstrated. In contrast to various other "square root of time" release kinetics, the constant of proportionality in the classical Higuchi equation has a specific, physically realistic meaning. The major benefits of this equation include the possibility to: (i) facilitate device optimization, and (ii) to better understand the underlying drug release mechanisms. The equation can also be applied to other types of drug delivery systems than thin ointment films, e.g., controlled release transdermal patches or films for oral controlled drug delivery. Later, the equation was extended to other geometries and related theories have been proposed. The aim of this review is to highlight the assumptions the derivation of the classical Higuchi equation is based on and to give an overview on the use and potential misuse of this equation as well as of related theories.

Lipid dosage forms provide an interesting potential for controlled drug delivery. In contrast to frequently used poly(ester) based devices for parenteral administration, they do not lead to acidification upon degradation and potential drug inactivation, especially in the case of protein drugs and other acid-labile active agents. The aim of this article is to give an overview on the current state of the art of mathematical modeling of drug release from this type of advanced drug delivery systems. Empirical and semi-empirical models are described as well as mechanistic theories, considering diffusional mass transport, potentially limited drug solubility and the leaching of other, water-soluble excipients into the surrounding bulk fluid. Various practical examples are given, including lipid microparticles, beads and implants, which can successfully be used to control the release of an incorporated drug during periods ranging from a few hours up to several years. The great benefit of mechanistic mathematical theories is the possibility to quantitatively predict the effects of different formulation parameters and device dimensions on the resulting drug release kinetics. Thus, in silico simulations can significantly speed up product optimization. This is particularly useful if long release periods (e.g., several months) are targeted, since experimental trial-and-error studies are highly time-consuming in these cases. In the future it would be highly desirable to combine mechanistic theories with the quantitative description of the drug fate in vivo, ideally including the pharmacodynamic efficacy of the treatments.

Lipid implants prepared by melting and casting offer a great potential for advanced drug delivery. However, care must be taken with respect to the solid state of the lipid(s) and potential changes thereof during storage. Generally, a thermal aftertreatment is required. However, little is known about the impact of the curing time and temperature on drug release. The aim of this study was to better understand the importance of these parameters for different types of implants containing propranolol hydrochloride. Hydrogenated cottonseed oil and hydrogenated soybean oil were used as matrix formers. The implants were characterized with respect to their in vitro release kinetics, water uptake, thermal properties, and morphology. On the basis of these experimental results, a mechanistic mathematical model was used to gain further insight into the underlying mass transport mechanisms. Both the curing time and the temperature strongly affected the resulting drug release patterns. Importantly, in most cases, these effects could not be attributed to polymorph transformations but to changes in the implants' microstructure. The size of the lipid particles depended on both the curing time and the temperature, and determined the size of the pores/channels through which water and drug diffuse. The importance of this aspect is often underestimated.

The aim of this study was to simultaneously control the release of multiple vitamins exhibiting very different water-solubility and molecular weights from multiparticulates. Several types of sucrose esters and triglycerides were studied as matrix formers in granules prepared by wet granulation, melt granulation or compression and grinding. The vitamin release kinetics were measured in 0.1N HCl, phosphate buffer pH 6.8 and water in a USP paddle apparatus. An appropriate analytical solution of Fick's second law of diffusion was used to better understand the underlying mass transport phenomena. Importantly, the release rates of nicotinamide, pyridoxine hydrochloride, riboflavin 5'-phosphate, riboflavin, thiamine chloride hydrochloride and thiamine nitrate can simultaneously be controlled from the investigated multiparticulates. Varying the total vitamin content, granule size, type of preparation technique and type of matrix former (Sucrose Stearate S370, Sucrose Stearate S1170, glycerol dibehenate, glycerol dipalmitostearate), desired vitamin release rates can be adjusted. Interestingly, diffusion seems to be the dominant mass transport mechanism in most cases. Thus, appropriate solutions of Fick's law can be used to quantitatively predict the effects of the systems' composition and dimensions on the resulting vitamin release patterns. This knowledge can significantly help facilitating device optimization.

Yet, no standardized test method for drug release measurements from PLGA-based microparticles has been generally agreed on, or described by the regulatory authorities. Often, perfect sink conditions are provided in vitro to avoid artificial drug saturation effects. However, the maintenance of such conditions might strongly affect PLGA degradation. The involved physicochemical processes are complex and the potential impact of perfect sink conditions is not yet well understood. Differently sized, highly porous, carbamazepine- and ibuprofen-loaded PLGA microparticles were prepared by a W/O/W emulsion solvent extraction/evaporation technique. The initial drug loading was intentionally low (3–4%) so that the two drugs were molecularly dispersed within the polymeric matrices (monolithic solutions). This was important to be able to exclude potential limited drug solubility effects on the resulting release kinetics. Drug release into phosphate buffer pH 7.4 was measured under perfect sink conditions. SEC, DSC and SEM were used to characterize polymer degradation. The decrease in the average polymer molecular weight, glass transition temperature as well as changes in the inner and outer morphology of the PLGA microparticles were strongly affected by the bulk fluid's volume. In the case of the poorly water-soluble drug carbamazepine, much lower “microparticle mass:phosphate buffer volume” ratios were required to maintain perfect sink conditions, resulting in stable pH values within the bulk fluid, slower PLGA degradation and, thus, lower drug release rates. Thus, great care has to be taken when defining the conditions for in vitro drug release measurements from PLGA-based microparticles, avoiding potentially artificial conditions for polymer degradation.

The aim of this study was to elucidate the mass transport mechanisms controlling drug release from compressed lipid implants. The latter steadily gain in importance as parenteral controlled release dosage forms, especially for acid-labile drugs. A variety of lipid powders were blended with theophylline and propranolol hydrochloride as sparingly and freely water-soluble model drugs. Cylindrical implants were prepared by direct compression and thoroughly characterized before and after exposure to phosphate buffer pH 7.4. Based on the experimental results, an appropriate mathematical theory was identified in order to quantitatively describe the resulting drug release patterns. Importantly, broad release spectra and release periods ranging from 1 d to several weeks could easily be achieved by varying the type of lipid, irrespective of the type of drug. Interestingly, diffusion with constant diffusivities was found to be the dominant mass transport mechanism, if the amount of water within the implant was sufficient to dissolve all of the drug. In these cases an analytical solution of Fick's second law could successfully describe the experimentally measured theophylline and propranolol hydrochloride release profiles, even if varying formulation and processing parameters, e.g. the type of lipid, initial drug loading, drug particles size as well as compression force and time. However, based on the available data it was not possible to distinguish between drug diffusion control and water diffusion control. The obtained new knowledge can nevertheless significantly help facilitating the optimization of this type of advanced drug delivery systems, in particular if long release periods are targeted, which require time consuming experimental trials.

Film coating thickness and terahertz electric field peak strength (TEFPS) were determined using terahertz pulsed imaging (TPI) and employed for the analysis of sustained-release coated pellets (theophylline layered sugar cores coated with Kollicoat SR:Kollicoat IR polymer blends). The effects of coating thickness, drug layer uniformity and optional curing were investigated using eight batches of pellets. Ten pellets from each batch were imaged with TPI to analyse the coating morphology (depicted in TEFPS) and thickness prior to release measurements. The results showed TEFPS values of 15.8% and 14.5% for pellets with a smooth drug layer coated at 8.2 and 12.5% (w/w) polymer weight-gain, respectively. Whereas 6.7% was derived for pellets with a coarse drug layer coated at both weight-gains. Although there were major differences in TEFPS, the resulting drug release kinetics were very similar. It was also shown that a 36 microm coating thickness difference was not drug release rate determining. These results suggested that drug release for the pellets studied was not predominately governed by drug diffusion through the polymeric film coating but probably to a large extent limited by drug solubility. TPI proved to be highly suitable to detect non-homogeneities in the drug layer and polymeric film coating.

The aim of this study was to better understand the interactions between metoprolol tartrate and quaternary polymethacrylate (Eudragit RL and Eudragit RS) films. For reasons of comparison, polymeric films containing the free base metoprolol or free tartaric acid were also prepared. Systems containing various amounts of the free base, free acid and the salt were characterised using polarising light microscopy, X-ray powder diffraction, differential scanning calorimetry and mechanical analysis (puncture test). The free base is the most efficient plasticiser of the three species for Eudragit RL and Eudragit RS, but with limited solubility in the polymers. Due to its hydrophobicity, it can interact with the hydrophobic polymer backbones. In contrast, in salt containing films, ionic interactions between the positively charged quaternary ammonium groups and the negatively charged tartrate anions apparently occur, this being suggested by the different effects on Eudragit RL versus RS, which have different contents of quaternary ammonium groups. Importantly, the combination of acid and base as a salt avoids drug precipitation at higher metoprolol contents. The obtained new insight into the occurring drug-polymer interactions can help to facilitate the development/optimisation of this type of dosage forms.

Different types of ethylcellulose-based mini-matrices were prepared by hot-melt extrusion and thoroughly characterized in vitro. Metoprolol tartrate was used as model drug, and various amounts and types of polyethylene glycol (PEG)/polyethylene oxide (PEO) were added as release rate modifiers. Based on the experimental results, appropriate mathematical theories were identified/developed, allowing for a better understanding of the underlying drug release mechanisms. For instance, it could be shown that at high initial PEG/PEO contents and/or intermediate initial PEG/PEO contents of low molecular weight, drug diffusion with time- and position-independent diffusivities is predominant. In contrast, at low initial PEG/PEO contents and intermediate initial PEG/PEO contents of high molecular weight, the time- and position-dependent dynamic changes in the matrix porosities significantly affect the conditions for drug and PEG/PEO diffusion. These dynamic changes must be taken into account in the mathematical model. Importantly, the proposed theories are mechanistic realistic and also allow for the quantitative prediction of the effects of the device design on the resulting drug release patterns. Interestingly, these quantitative predictions could be confirmed by independent experiments. Furthermore, Raman spectroscopy allowed for the determination of the resulting drug concentration-position profiles within the mini-matrices as a function of time and confirmed the theoretical predictions.

Microcrystalline cellulose (MCC) is a well-established pelletisation aid. However, MCC pellets generally do not disintegrate, resulting in prolonged drug release, especially in the case of drugs with poor/low aqueous solubility. The major objectives of this study were (i) to modify the prolonged matrix-type drug release from MCC pellets by addition of a disintegrant (croscarmellose Na) or pore former (PEG 6000), (ii) to evaluate carrageenan as potential alternative pelletisation aid for manufacturing high-dose immediate release pellets, and (iii) to better understand the underlying drug release mechanisms. Pellets containing 77-90% drug with poor/low aqueous solubility (vatalanib succinate, SAG/ZK, or theophylline) were prepared by extrusion-spheronisation. All batches showed acceptable yields, aspect ratios, tensile strengths, and porosities. Drug release from MCC pellets was predominantly controlled by pure diffusion and limited drug solubility and could be quantitatively described using Fick's law. Importantly, the apparent drug diffusivity could effectively be adjusted by adding small amounts of a disintegrant or pore former, allowing for release periods ranging from a few minutes to several hours. The drug diffusion coefficients varied between 0.36 and 29 x 10(-6)cm(2)/s. In contrast, carrageenan-based pellets very rapidly disintegrated upon contact with aqueous media and released high doses of drugs with poor/low aqueous solubility within a few minutes.

The aim of this study was to elucidate the underlying drug release mechanisms in pellets coated with aqueous ethylcellulose dispersion, providing long term stable drug release profiles and containing different types of starter cores. The systems were thoroughly characterized using mechanical analysis; the sensitivity of drug release to the osmolality of the release medium was measured; scanning electron microscopy and optical macroscopy were used to monitor the pellets' morphology and dimensions upon exposure to different media, and drug release was measured from single and ensembles of pellets as well as from thin, free films. All experimental results indicate that diltiazem HCl release from pellets coated with ethylcellulose containing small amounts of poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer is primarily controlled by drug diffusion through the intact polymeric membranes, irrespective of the type of starter core (consisting of microcrystalline cellulose or sugar, optionally coated with ethylcellulose). Importantly, the apparent diffusion coefficient of the drug in the macromolecular networks could easily be determined with thin free films and successfully be used to quantitatively predict the release rate from coated pellets. Thus, based on this knowledge and using the presented mathematical theories the development of new/ optimization of existing controlled drug delivery systems of this type can be significantly facilitated.

The major aim of this study was to identify an easy tool to improve the long term stability of polymeric film coatings applied from aqueous dispersions. Drug release profiles from ethylcellulose-coated theophylline pellets were monitored during 6 months open storage under ambient and stress conditions ["room temperature/ambient relative humidity (RH)" and "40 degrees C/75%RH"]. The pellets were cured for I or 2 d at 60 degrees C or for 1 or 2 d at 60 degrees C/75%RH (followed by 1 d at 60 degrees C for drying). Drug release was measured in 0.1 M HCl and in phosphate buffer pH 7.4. Interestingly, the addition of only small amounts of poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer provided stable drug release profiles under all the investigated conditions, irrespective of the type of release medium, coating level, polymer blend ratio and curing conditions. The addition of small amounts of propylene glycol alginate resulted in unaltered drug release kinetics during open storage under ambient conditions, but decreasing theophylline release rates during open storage under stress conditions, due to further gradual polymer particle coalescence. When adding small amounts of carrageenan to the ethylcellulose coatings, essentially stable theophylline release patterns (with slight variations) were obtained. As coating conditions were not optimized for each system, further work is necessary to distinguish polymer from process effects. The observed stabilizing effects of the investigated added polymers might be attributable to their hydrophilic nature, trapping water within the coatings during film formation and, thus, facilitating polymer particle coalescence. This new concept can be used to overcome one of the major practical obstacles associated with aqueous polymeric film coatings today: storage instability. (C) 2007 Elsevier B.V. All rights reserved.

The use of polymer blends as coating materials for controlled drug delivery systems can offer major advantages, including: (i) facilitated adjustment of desired drug release patterns, mechanical properties and drug release mechanisms, (ii) improved film formation and storage stability, and (iii) the possibility to develop novel strategies for site specific drug delivery within the gastro intestinal tract (e.g., colon targeting). However, these systems are more complex than coatings based on only one polymer and care has to be taken when using this type of formulations. For instance, the blended polymers can be incompatible, aqueous polymer dispersions might flocculate and plasticizers potentially redistribute from one polymer into the other during curing and/or long term storage. This article gives an overview on the current state of the art of the use of polymer blends as coating materials for controlled drug delivery, explaining the major advantages and potential pitfalls. Special emphasis is laid on the underlying drug release mechanisms and practical examples for various types of applications are given. Due to the higher complexity of the systems, a thorough understanding of the most important mass transport phenomena involved in the control of drug release can be very helpful to render the optimization of this type of advanced delivery systems more efficient.

The objective of the present study was to investigate and quantify the effects of ibuprofen, chlorpheniramine maleate and metoprolol tartrate on the thermal, mechanical and diffusional properties of polyacrylate-based films. Thin drug-containing films were prepared from organic Eudragit RS solutions and physicochemically characterized with respect to their glass transition temperature, mechanical properties and drug release kinetics in phosphate buffer pH 7.4. The apparent diffusion coefficient of the drug within the polymeric systems was determined by fitting an adequate solution of Fick's second law of diffusion to the experimentally determined release profiles. Importantly, the glass transition temperature of the films significantly decreased with increasing initial drug content, whereas the film flexibility and drug release rate increased. This clearly indicates that the three drugs act as efficient plasticizers for Eudragit RS. Interestingly, the mathematical analysis revealed that drug release was primarily controlled by diffusion. An increase in the initial drug content resulted in increased drug diffusivities and, thus, accelerated (absolute and relative) drug release rates. Importantly, quantitative relationships could be established between the drug diffusivity and the initial drug content. Based on this knowledge, the effects of the films' composition and thickness on the resulting drug release kinetics (also from coated solid dosage forms) can be predicted in a quantitative way.

The mass transport mechanisms involved in the controlled delivery of drugs to living brain tissue are complex and yet not fully understood. Often the drug is embedded within a polymeric or lipidic matrix, which is directly administered into the brain tissue, that is, intracranially. Different types of systems, including microparticles and disc- or rod-shaped implants are used to control the release rate and, thus, to optimize the drug concentrations at the site of action in the brain over prolonged periods of time. Most of these dosage forms are biodegradable to avoid the need for the removal of empty remnants after drug exhaustion. Various physical and chemical processes are involved in the control of drug release from these systems, including water penetration, drug dissolution, degradation of the matrix and drug diffusion. Once the drug has been released from the delivery system, it has to be transported through the living brain tissue to the target site(s). Again, a variety of phenomena, including diffusion, drug metabolism and degradation, passive or active uptake into CNS tissue and convection can be of importance for the fate of the drug. An overview is given of the current knowledge of the nature of barriers to free access of drug to tumour sites within the brain and the state of the art of: (i) mathematical modeling approaches describing the physical transport processes and chemical reactions which can occur in different types of intracranially administered drug delivery systems, and of (ii) theories quantifying the mass transport phenomena occurring after drug release in the living tissue. Both, simplified as well as complex mathematical models are presented and their major advantages and shortcomings discussed. Interestingly, there is a significant lack of mechanistically realistic, comprehensive theories describing both parts in detail, namely, drug transport in the dosage form and in the living brain tissue. High quality experimental data on drug concentrations in the brain tissue are difficult to obtain, hence this is itself an issue in testing mathematical approaches. As a future perspective, the potential benefits and limitations of these mathematical theories aiming to facilitate the design of advanced intracranial drug delivery systems and to improve the efficiency of the respective pharmacotherapies are discussed.

The aim of this study was to prepare different types of paclitaxel-loaded, PLGA-based microparticles and lipidic implants, which can directly be injected into the brain tissue. Releasing the drug in a time-controlled manner over several weeks, these systems are intended to optimize the treatment of brain tumors. The latter is particularly difficult because of the blood-brain barrier (BBB), hindering most drugs to reach the target tissue upon systemic administration. Especially paclitaxel (being effective for the treatment of ovarian, breast, lung and other cancers) is not able to cross the BBB to a notable extent since it is a substrate of the efflux transporter P-glycoprotein. Both, biodegradable microparticles as well as small, cylindrical, glycerol tripalmitate-based implants (which can be injected using standard needles) were prepared with different paclitaxel loadings. The effects of several formulation and processing parameters on the resulting drug release kinetics were investigated in phosphate buffer pH 7.4 as well as in a diethylnicotinamide (DENA)/phosphate buffer mixture. Using DSC, SEM, SEC and optical microscopy deeper insight into the underlying drug release mechanisms could be gained. The presence of DENA in the release medium significantly increased the solubility of paclitaxel, accelerated PLGA degradation, increased the mobility of the polymer and drug molecules and fundamentally altered the geometry of the systems, resulting in increased paclitaxel release rates.

THE OBJECTIVES OF THIS STUDY WERE: (i). to use blends of gastrointestinal tract (GIT)-insoluble and enteric polymers (ethyl cellulose and Eudragit L) as coating materials for multiparticulate controlled release dosage forms; (ii). to investigate the effects of the polymer blend ratio and coating level on the resulting drug release patterns; and (iii). to explain the observed phenomena based on the physicochemical properties of the systems. Propranolol HCl-loaded pellets were coated in a fluidized bed coater with organic polymer solutions; thin, drug-containing and drug-free, polymeric films were prepared using a casting knife. In vitro drug release, water uptake and dry weight loss studies were performed in 0.1 M HCl and phosphate buffer pH 7.4, respectively. The apparent drug diffusion coefficients within the polymeric systems were determined using different experimental and theoretical techniques (side-by-side diffusion cells, in vitro drug release from thin films; exact and approximate solutions of Fick's second law of diffusion). A broad range of drug release patterns from coated pellets could be achieved by varying the GIT-insoluble:enteric polymer blend ratio. With increasing relative amounts of Eudragit L, the release rates in both media significantly increased. The increase at low pH could be attributed to an increase in water uptake, as observed with thin films. Interestingly, only partial Eudragit L leaching occurred in phosphate buffer pH 7.4 even at high enteric polymer contents, indicating that the GIT-insoluble polymer effectively hindered the dissolution of the entrapped Eudragit L. At high pH, both polymer leaching and polymer swelling contributed to the control of drug release. The determined apparent drug diffusion coefficients take the two effects adequately into account.

Shellac is a natural polymer, which is used as enteric coating material in pharmaceutical applications. The major objective of the present study was to investigate the potential of shellac for other purposes, namely to provide moisture-protective and taste-masking coatings as well as extended-release matrix tablets. The efficiency of shellac to achieve moisture protection and taste masking was compared with that of hydroxypropyl methylcellulose (HPMC), which is most frequently used for these purposes. Shellac-coated tablets showed lower water uptake rates than HPMC-coated systems at the same coating level. The stability of acetylsalicylic acid was higher in tablets coated with shellac compared with HPMC-coated systems, irrespective of the storage humidity. Therefore, lower shellac coating levels were required to achieve the same degree of drug protection. Shellac coatings effectively masked the unpleasant taste of acetaminophen tablets. Compared to HPMC, again lower coating levels were required to achieve similar effects. The resulting drug release in simulated gastric fluid was not significantly altered by the thin shellac coatings, which rapidly ruptured due to the swelling of the coated tablet core. In addition, shellac was found to be a suitable matrix former for extended-release tablets. The latter could be prepared by direct compression or via wet granulation using ethanolic or ammoniated aqueous shellac binder solutions. The resulting drug-release patterns could effectively be altered by varying different formulation and processing parameters.

HPMC-, PVPVA- and PVP-based microparticles loaded with 30% ketoprofen were prepared by spray drying suspensions or solutions in various water:ethanol blends. The inlet temperature, drying gas and feed flow rates were varied. The resulting differences in the ketoprofen release rates in 0.1 M HCl could be explained based on X-ray diffraction, mDSC, SEM and particle size analysis. Importantly, long term stable drug release could be provided, being much faster than: (i) drug release from a commercial reference product, (ii) the respective physical drug:polymer mixtures, as well as (iii) the dissolution of ketoprofen powder as received. In addition, highly supersaturated release media were obtained, which did not show any sign for re-crystallization during the observation period. Surprisingly, spraying suspensions resulted in larger microparticles exhibiting faster drug release compared to spraying solutions, which resulted in smaller particles exhibiting slower drug release. These effects could be explained based on the physico-chemical characteristics of the systems.

The aim of this study was to develop new multi-layer matrix tablets to achieve bimodal drug release profiles (fast release/slow release/fast release). Hydroxypropyl methylcellulose acetate succinate (HPMCAS, type MF) was chosen as a matrix former, because it is water-insoluble at low, and water-soluble at high pH values. Studies focused on the elucidation of the drug release mechanisms from HPMCAS-MF:drug tablets. In 0.1 N HCl the resulting release kinetics can be described using Fick’s second law of diffusion, taking into account axial and radial mass transfer in cylindrical geometry. As the diffusion coefficients are found to be constant and the boundary conditions to be stationary, these systems are purely drug diffusion-controlled. In contrast, the dominating mass transport phenomena in phosphate buffer pH 7.4 are more complex. Due to polymer dissolution the resulting matrix structure is time-variant, leading to increasing drug diffusion coefficients and decreasing tablet dimensions, and thus moving boundary conditions. Drug release is affected by water imbibition, drug diffusion and polymer dissolution and is faster compared to 0.1 N HCl. With knowledge of these underlying release mechanisms, multi-layer matrix tablets were developed to achieve bimodal drug release. HPMCAS-MF:drug mixtures were used as tablet cores. As expected, changing the release medium from 0.1 N HCl to phosphate buffer pH 7.4 after 2 h, lead to a significant increase in drug release. The abruptness of this rate change could be enhanced by adding two drug-free HPMCAS-MF barrier layers (one on each side) to the system. The addition of a fourth, drug-containing and fast disintegrating initial dose layer yielded the desired bimodal drug release patterns. The process and formulation parameters affecting the resulting release rates were investigated using theophylline and acetaminophen as model drugs.

Purpose. The purpose of this study was to investigate the drug release mechanisms from hydroxypropyl methylcellulose (HPMC)-matrices, and to develop a new model for quantitative predictions of controlled drug delivery. Methods. The dissolved mass of pure HPMC-matrices and the drug release rate from propranolol HCl-loaded HPMC-matrices were determined experimentally. Based on Fick's second law of diffusion for cylinders, the transport of water and drug were modeled considering (i) both radial and axial diffusion, (ii) concentration-dependent drug diffusivities, (iii) matrix swelling and (iv) HPMC dissolution. Results. Good agreement between theory and experiment (dissolved mass and drug release studies) was obtained, proving the validity of the presented model. The water and drug diffusivities are strongly dependent on the matrix swelling ratio. Diffusion, swelling and dissolution are the governing mechanisms involved in the overall drug release process. Conclusions. The practical benefit of the presented model is to identify the required shape and dimensions of drug-loaded HPMC-matrices in order to achieve desired release profiles, thus facilitating the development of new controlled drug delivery products. This will be demonstrated in a future study.

The treatment of patients suffering from advanced Parkinson's disease is highly challenging, because the efficacy of the "gold standard" levodopa declines with time. Co-administration of the dopamine receptor agonist apomorphine is beneficial, but difficult due to the poor oral bioavailability and short half-life of this drug. In order to overcome these restrictions, PLGA-based microparticles allowing for controlled parenteral delivery of this morphine derivative were prepared using (solid-in-)oil-in-water extraction/evaporation techniques. Particular attention was paid to minimize spontaneous oxidation of the labile drug and to optimize the key features of the microparticles, including encapsulation efficiency, initial burst release and particle size. Various formulation and processing parameters were adjusted in this respect. The systems were thoroughly characterized using SEM, EDX, DSC, laser diffraction, headspace-GC as well as in vitro drug release measurements in agitated flasks and flow-through cells. Importantly, apomorphine could effectively be protected against degradation during microparticle preparation and within the delivery systems upon exposure to phosphate buffer pH 7.4 (containing 0.2% ascorbic acid) at 37 °C: 90% intact drug was released at a constant rate during about 10d.

MALDI-TOF MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) imaging is used to characterize novel lipid implants allowing for controlled drug delivery. Importantly, this innovative technique provides crucial information on the inner structure of the implants before and after exposure to the release medium and does not require the addition of marker substances. Implants were prepared by extrusion at room temperature. Thus, in contrast to hot-melt extruded systems, the risks of drug inactivation and solid state transformations of the lipid matrix former are reduced. Hydrogenated/hardened soybean oil and glyceryl tristearate were studied as lipids and propranolol hydrochloride and theophylline as drugs, exhibiting significantly different solubility in water. The implants were also characterized by optical microscopy, differential scanning calorimetry, water uptake and lipid erosion studies, mathematical modeling as well as in vitro drug release measurements. Importantly, broad spectra of drug release patterns with release periods ranging from a few days up to several months could easily be provided when varying the initial drug content and type of lipid, irrespective of the type of drug. The diameter of the implants can be as small as 1 mm, facilitating injection. MALDI-TOF MS imaging revealed homogeneous macroscopic drug distributions within the systems, but steep drug concentration gradients in radial and axial direction at the lower micrometer level, indicating drug- and lipid-rich domains. As the implants do not significantly swell, local irritation upon administration due to mechanical stress can be expected to be limited. Good agreement between experimentally measured and theoretically calculated drug release kinetics revealed that diffusional mass transport plays a major role for the control of drug release from this type of advanced drug delivery systems.

When using aqueous polymer dispersions for the preparation of controlled-release film coatings, instability during long-term storage can be a crucial concern. Generally, a thermal after treatment is required to assure sufficient polymer particle coalescence. This curing step is often performed under static conditions in an oven, which is a time-consuming and rather cumbersome process. Dynamic curing in the fluidized bed presents an attractive alternative. However, yet little is known on the required conditions, in particular: temperature, time, and relative humidity, to provide stable film structures. The aim of this study was to better understand the importance of these key factors and to evaluate the potential of dynamic curing compared with that of static curing. Recently proposed ethylcellulose:poly(vinyl alcohol)–poly(ethylene glycol) graft copolymer (PVA–PEG graft copolymer) dispersions were coated on theophylline and metoprolol succinate-loaded starter cores, exhibiting different osmotic activity. Importantly, processing times as short as 2 h were found to be sufficient to provide long-term stable films, even upon open storage under stress conditions. For instance, 2-h dynamic curing at 57 °C and 15% relative humidity are assuring stable film structures in the case of theophylline matrix cores coated with 15% ethylcellulose:PVA–PEG graft copolymer 85:15. Importantly, the approach is also applicable to other types of drugs and starter cores, and the underlying drug release mechanisms remain unaltered.

The aim of this study was to use lipid:lipid blends as matrix formers in controlled release implants. The systems were prepared by melting and casting and thoroughly characterized before and after exposure to the release medium. Based on the experimental results, a mechanistic realistic mathematical model was used to get further insight into the underlying drug release mechanisms. Importantly, broad spectra of drug release patterns could be obtained by simply varying the lipid:lipid blend ratio in implants based on Precirol ATO 5 (glyceryl palmitostearate):Dynasan 120 (hardened soybean oil) mixtures loaded with propranolol hydrochloride. Release periods ranging from a few days up to several months could be provided. Interestingly, the drug release rate monotonically decreased with increasing Dynasan 120 content, except for implants containing about 20–25% Precirol, which exhibited surprisingly high release rates. This could be attributed to the incomplete miscibility of the two lipids at these blend ratios: DSC thermograms showed phase separation in these systems. This is likely to cause differences in the implants’ microstructure, which determines the mobility of water and dissolved drug as well as the mechanical stability of the systems. Purely diffusion controlled drug release was only observed at Precirol ATO 5 contents around 5–10%. In all other cases, limited drug solubility effects or matrix former erosion are also expected to play a major role. Thus, lipid:lipid blends are very interesting matrix formers in controlled release implants. However, care must be taken with respect to the mutual miscibility of the compounds: in case of phase separation, surprisingly high drug release rates might be observed.

The aim of this work was to better understand which physicochemical processes are involved in the control of drug release from lipid implants prepared by melting and casting. Lipid implants gain steadily in importance as controlled parenteral drug delivery systems: In contrast to PLGA-based devices, no acidic microclimates are created, which can inactivate incorporated drugs. The melting and casting method offers various advantages over the commonly used direct compression technique. For example, powder de-mixing during manufacturing and highly challenging scale-up due to poor powder flowability are avoided. Importantly, broad spectra of drug release patterns can be easily provided by varying the type of lipid. The resulting drug release rates are generally lower than those of implants prepared by direct compression. This is probably due to the differences in the microstructure of the pore network of the systems. Drug or water diffusion plays a dominant role for the control of drug release, potentially combined with limited drug solubility effects, caused by the low amounts of water available within the implants. In the case of pure diffusion control, a mechanistic realistic mathematical theory is proposed, which allows for quantitative predictions of the effects of formulation parameters on the resulting drug release kinetics. Importantly, these theoretical predictions could be successfully confirmed by independent experiments. Thus, the obtained new insight into the underlying drug release mechanisms can significantly facilitate the optimization of this type of advanced drug delivery systems. This is particularly helpful if long release periods are targeted, requiring time-consuming experimental studies.

Kollidon ® SR-based matrix tablets containing various amounts of diprophylline were prepared and thoroughly characterized in vitro. This includes drug release measurements in 0.1 M HCl and phosphate buffer pH 7.4, monitoring of changes in the tablet's height and diameter, morphology as well as dry mass upon exposure to the release media. Based on these experimental results, a mechanistic realistic mathematical theory is proposed, taking into account the given initial and boundary conditions as well as radial and axial mass transport in cylinders. Importantly, good agreement between theory and experiment was obtained in all cases, indicating that drug diffusion with constant diffusivity is the dominant mass transport mechanism in these systems. Furthermore, the proposed theory was used to quantitatively predict the effects of the initial tablet height and diameter on the resulting drug release patterns. These theoretical predictions were compared with independently measured drug release kinetics. Good agreement was observed in all cases, proving the validity of the mathematical theory and illustrating the latter's practical benefit: The model can help to significantly facilitate the recipe optimization of this type of advanced drug delivery systems in order to achieve a desired release profile.

The objective of this study was to produce sustained-release matrix tablets by means of injection moulding and to evaluate the influence of matrix composition, process temperature and viscosity grade of ethylcellulose on processability and drug release by means of a statistical design. The matrix tablets were physico-chemically characterized and the drug release mechanism and kinetics were studied. Formulations containing metoprolol tartrate (30%, model drug), ethylcellulose with dibutylsebacate (matrix former and plasticizer) and L-HPC were extruded and subsequently injection moulded into tablets (375mg, 10mm diameter, convex-shaped) at different temperatures (110, 120 and 130 degrees C). Dissolution tests were performed and tablets were characterized by means of DSC, X-ray powder diffraction studies, X-ray tomography, porosity and hardness. Tablets containing 30% metoprolol and 70% ethylcellulose (EC 4cps) showed an incomplete drug release within 24h (