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Dexamethasone-loaded silicone matrices offer an interesting potential as innovative drug delivery systems, e.g. for the treatment of inner ear diseases or for pacemakers. Generally, very long drug release periods are targeted: several years/decades. This renders the development and optimization of novel drug products cumbersome: experimental feedback on the impact of the device design is obtained very slowly. A better understanding of the underlying mass transport mechanisms can help facilitating research in this field. A variety of silicone films were prepared in this study, loaded with amorphous or crystalline dexamethasone. Different polymorphic drug forms were investigated, the film thickness was altered and the drug optionally partially/completely exchanged by much more water-soluble dexamethasone ‘phosphate’. Drug release studies in artificial perilymph, scanning electron microscopy, optical microscopy, differential scanning calorimetry, X-ray diffraction and Raman imaging were used to elucidate the physical states of the drugs and polymer, and of the systems’ structure as well as dynamic changes thereof upon exposure to the release medium. Dexamethasone particles were initially homogeneously distributed throughout the systems. The hydrophobicity of the matrix former very much limits the amounts of water penetrating into the system, resulting in only partial drug dissolution. The mobile drug molecules diffuse out into the surrounding environment, due to concentration gradients. Interestingly, Raman imaging revealed that even very thin silicone layers (

Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D2 receptor DP1 signaling mechanism during infancy to recruit newborn astrocytes that ‘escort’ them into adulthood, and that the impairment of postnatal hypothalamic gliogenesis markedly alters sexual maturation by preventing this recruitment, a process mimicked by the endocrine disruptor bisphenol A. Inhibition of DP1 signaling in the infantile preoptic region, where GnRH cell bodies reside, disrupts the correct wiring and firing of GnRH neurons, alters minipuberty or the first activation of the hypothalamic–pituitary–gonadal axis during infancy, and delays the timely acquisition of reproductive capacity. These findings uncover a previously unknown neuron-to-neural-progenitor communication pathway and demonstrate that postnatal astrogenesis is a basic component of a complex set of mechanisms used by the neuroendocrine brain to control sexual maturation. GnRH neurons control their own connectivity and function as well as the sexual maturation of the individual by using prostaglandin D2 DP1 signaling to recruit and stably associate with newborn astrocytes in the preoptic region during infancy in rodents.

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Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D

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Polymeric film coatings based on quaternary polymethacrylates (QPMs, e.g. Eudragits®) are frequently used for controlled release applications. However, their considerable sticking tendency is a major drawback in practice. In this study, different amounts of magnesium aluminum silicate (MAS) were added to the film coatings in order to overcome this hurdle. MAS is negatively charged and can electrostatically interact with the positively charged QPM. Different types of tablet cores were coated with aqueous Eudragit® RL 30D dispersions, optionally containing varying amounts of MAS. Dynamic changes in the wet mass of the systems as well as drug release upon exposure to 0.1 M HCl and phosphate buffer pH 6.8 were monitored. Propranolol HCl, acetaminophen, and diclofenac sodium were used as cationic, nonionic and anionic model drugs. The tablets were optionally cured for 12 h at 45 or 60 °C. Importantly, the addition of MAS to aqueous Eudragit® RL 30D dispersion substantially reduced the films’ stickiness and led to stable inner coating structures, even without curing. Desired drug release rates can be adjusted by varying the QPM:MAS ratio and coating level.

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., Graphical abstract Unlabelled Image

Cochlear implant is the method of choice for the rehabilitation of severe to profound sensorineural hearing loss. The study of the tissue response to cochlear implantation and the prevention of post-cochlear-implant damages are areas of interest in hearing protection research. The objective was to assess the efficacy of dexamethasone-eluting electrode array on endo canal fibrosis formation by three-dimensional immunofluorescence analysis in implanted Mongolian gerbil cochlea. Two trials were conducted after surgery using Mongolian gerbil implanted with dexamethasone-eluting or non-eluting intracochlear electrode arrays. The animals were then euthanised 10 weeks after implantation. The cochleae were prepared (electrode array in place) according to a 29-day protocol with immunofluorescent labelling and tissue clearing. The acquisition was carried out using light-sheet microscopy. Imaris software was then used for three-dimensional analysis of the cochleae and quantification of the fibrotic volume. The analysis of 12 cochleae showed a significantly different mean volume of fibrosis (2.16 × 108 μm3 ± 0.15 in the dexamethasone eluting group versus 3.17 × 108 μm3 ± 0.54 in the non-eluting group) (p = 0.004). The cochlear implant used as a corticosteroid delivery system appears to be an encouraging device for the protection of the inner ear against fibrosis induced by implantation. Three-dimensional analysis of the cochlea by light-sheet microscopy was suitable for studying post-implantation tissue damage.

Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.

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.

International audience; The use of extracellular vesicles (EVs) for cardiac regenerative medicine as an alternative to cell transplantation has been demonstrated. For clinical applications, new translational issues have emerged such as parental cell selection, large-scale production, characterization, and delivery. Two main delivery approaches of EVs for heart repair can be used: either direct myocardial delivery in patients requiring surgery, or intravenous (IV) infusion. To potentiate EV beneficial effects, direct myocardial EV administration can be optimized by controlled-release biomaterials, whereas EV engineering should allow IV-injected EVs to be directed more specifically to the heart. However, new challenges include possible changes in EV bioactivity because of their interactions with the biomaterial, as well as the complexities of EV engineering to improve organ-specific targeting.There is increasing evidence that extracellular vesicles (EVs) mediate the paracrine effects of stem cells. Although EVs have several attractive characteristics, they also raise issues related to delivery. For patients with cardiac disease that require a surgical procedure, direct intramyocardial (IM) administration of EVs is straightforward but its efficacy may be limited by fast wash-out, hence the interest of incorporating EVs into a controlled release polymer to optimize their residence time. For patients without surgical indication, the intravenous (IV) route is attractive because of its lack of invasiveness; however, whole-body distribution limits the fraction of EVs that reach the heart, hence the likely benefits of EV engineering to increase EV homing to the target tissue.

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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.

International audience; Different types of hot melt extrudates were prepared based on a variety of blends of ethylcellulose with a 2nd polysaccharide, namely hydroxypropyl methylcellulose (HPMC), pectin, maize starch, inulin, maltodextrin, guar gum, and chitosan. In selected cases, the polymer:polymer blend ratio was varied from 80:20, 70:30, 60:40, 50:50, 40:60, 30:70 to 20:80. The addition of appropriate amounts of plasticizers allowed reducing the extrusion temperature to about 100 °C. The impacts of the screw speed, extrusion temperature, amount and type of plasticizer as well as of the amount and type of drug (10–60% theophylline or diprophylline) were studied. Drug release was measured in 0.1 M HCl for 2 h, followed by phosphate buffer pH 6.8 and (optionally) fecal samples to simulate the colon (under anaerobic conditions). DSC measurements and optical microscopy were used to characterize the physical state and morphology of the systems. Interestingly, hot melt extrudates based on ethylcellulose:guar gum blends could be easily prepared at a temperature of 100 °C and offered large spectra of drug release patterns for both: slightly water-soluble theophylline as well as freely water-soluble diprophylline. About constant drug release rates could be obtained during prolonged periods of time. Importantly, the resulting drug release rates from hot melt extrudates based on ethylcellulose:guar gum 80:20 blends were similar in the presence and absence of colonic bacteria, indicating that the ethylcellulose seems to protect the guar gum from degradation upon exposure to fecal samples. Furthermore, these systems were long term stable for at least 1 year under ambient conditions. Thus, they can offer an interesting potential as oral controlled drug delivery systems.

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.

International audience; Poly(lactic-co-glycolic acid) (PLGA)-based microparticles can be successfully used to control the release rate of a drug and optimize the therapeutic efficacy of a medical treatment. However, the underlying drug release mechanisms can be complex and are often not fully understood. This renders system optimization cumbersome. In this study, differently sized caffeine-loaded PLGA microparticles were prepared and the swelling and drug release behaviors of single microparticles were monitored upon exposure to phosphate buffer pH 7.4. Ensembles of microparticles were characterized by X-ray diffraction, differential scanning calorimetry, scanning electron microscopy, gel permeation chromatography, and optical microscopy. The observed triphasic drug release patterns could be explained as follows. The initial burst release can be attributed to the dissolution of tiny drug crystals with direct surface access. The subsequent second drug release phase (with an about constant release rate) could be attributed to the release of drug crystals in regions, which undergo local swelling. The third release phase (again rapid, leading to complete drug exhaust) could be explained by substantial polymer swelling throughout the systems. Once a critical polymer molecular weight is reached, the PLGA chains are sufficiently hydrophilic, insufficiently entangled and the osmotic pressure created by water soluble degradation products attracts high amounts of water into the system.

The aim of this study was to investigate the impact of the addition of very different types of additives on the key features of in-situ forming implants based on poly(D,L-lactic-co-glycolic acid) (PLGA, Resomer RG 502H) loaded with dexamethasone. All ingredients were dissolved in N-methyl-pyrrolidone (NMP), the implants formed upon solvent exchange. Crosslinked poly(acrylic acid) (Carbopol), poly(ethylene glycol) (PEG 400), hydroxypropyl methylcellulose (HPMC K100, HPMC E15), stearic acid and acetyltributyl citrate (ATBC) were studied as additives, in concentrations up to 5% (except for ATBC: up to 20%). Dynamic changes in the implants' wet mass, pH of the release medium, NMP leaching as well as dexamethasone release were monitored upon exposure to phosphate buffer pH 7.4. Also the implants’ inner and outer morphology was studied, using optical and scanning electron microscopy. Interestingly, the addition of the very different types of additives partially substantially altered the morphology and swelling kinetics of the investigated in-situ forming PLGA implants, whereas the impact on dexamethasone release was rather limited in all cases. Generally, the release rate slightly increased in the presence of the additives, only in the case of ATBC it slightly decreased. The overall limited effect on drug release might at least partially be attributed to the fact that: (i) water-soluble additives might rapidly leach out into the aqueous release medium during implant formation and/or promote implant swelling, and (ii) lipophilic additives might induce phase separation.

International audience; 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.

An oral colon delivery platform based on a novel combination strategy, leveraging multiple physiological characteristics of the intestine, is proposed. The system comprises a drug core, a water-swellable/soluble inner layer based on a hydrophilic cellulose derivative and an enteric outer layer (Eudragit® S) containing a microbially-degradable polysaccharide (high-amylose starch, Amylo N460), acting synergistically to prevent early release in the small intestine on the one hand, and release failure on the other. The Eudragit® S:Amylo N460 solid weight ratio in the external coating was 7:3; triethyl citrate and glyceryl monostearate were used as a plasticizer and an anti-tacking agent, respectively. The outer Eudragit® S/Amylo N460 layer was applied in a fluid bed using hydro-alcoholic or aqueous coating formulations. Two types of “inner” systems were studied: (i) Drug-loaded tablets coated with a low-viscosity hydroxypropyl methylcellulose (by aqueous spray-coating), and (ii) hydroxypropyl cellulose capsules prepared by injection-molding (filled with paracetamol as an analytical tracer). The obtained dosage forms were thoroughly characterized, including in vitro release measurements in various media. In all cases, pulsatile release profiles were obtained after medium change from 0.1 N HCl to phosphate buffer pH 7.4, with lag phases depending on the type and preparation technique of the hydrophilic polymer layer. The role of the microbiota on the release performance was explored in simulated colonic fluid (SCF), consisting in culture medium inoculated with fecal samples from inflammatory bowel disease patients. Clear differences in drug release were observed in SCF versus culture medium free of feces, indicating the effect of microbial degradation.

Chitosan and clays can form nanocomposites via electrostatic interactions, offering an interesting potential as advanced drug delivery systems. Such nanocomposites can be prepared in the form of microparticles using spray-drying. The objective of this study was to produce and characterize spray-dried chitosan-magnesium aluminum silicate (MAS) nanocomposite microparticles, loaded with propranolol HCl. The effects of the MAS content and addition of the crosslinking agent sodium tripolyphosphate (TPP) were investigated. The incorporation of MAS rendered the microparticles less spherical. The spray-dried particles exhibited an intercalated nanocomposite structure, the drug being dispersed in an amorphous form and/or dissolved in the systems. Interestingly, propranolol release was sustained during several hours from all types of microparticles in 0.1 M HCl and phosphate buffer pH 7.4, and no burst release was observed. This is rather surprising, because the particles were in the lower micrometer range, and chitosan is soluble at acidic pH. These results highlight the importance of “drug – chitosan” and “drug – MAS” interactions in this type of nanocomposite microparticles. With increasing MAS content drug release clearly slowed down at low and neutral pH, whereas the incorporation of 1–3% TPP caused only a slight/moderate decrease in the release rate, irrespective of the type of release medium.

Implants for controlled drug delivery can be very helpful to improve the therapeutic efficacy of a medical treatment, and at the same time reduce the risk of toxic side effects. In this article, four different strategies are exemplarily presented: hybrid bone substitutes combining hydroxyapatite and chitosan hydrogels; vascular stents coated with a bio-inspired polymer; cochlear implants for local dexamethasone delivery; and in-situ forming implants for periodontitis treatment. But this is only a restricted selection, and numerous other approaches and applications based on implants releasing a drug (or a combination of drugs) exist. Compared to conventional implants or pharmaceutical dosage forms, they might offer decisive advantages.

Poly(ethylene oxide) (PEO)-based hot melt extrudates offer an interesting potential as oral controlled drug delivery systems and can provide additional advantages, such as reducing the risk of drug abuse. Different polymer molecular weight PEOs are commercially available and can be used to prepare drug-loaded hot melt extrudates. Importantly, the macromolecular chain length impacts crucial system features, including the swelling and erosion kinetics of the systems, which determine the conditions for drug release. The aim of this study was to monitor the effects of changes in the PEO molecular weight (100, 200, 300, 600, 900, 1,000, 2,000, 4,000, 5,000, vs. 7000 kDa) on theophylline release from hot melt extrudates and to try to better understand the observed tendencies. The drug loading was kept constant at 10%. Interestingly, theophylline release substantially slowed down when increasing the PEO polymer molecular weight from 100 kDa to 600 kDa, but a further increase to 7000 kDa led only to a slight additional decrease in the drug release rate. Upon exposure to the release medium, a more or less important gel layer formed (depending on the PEO chain length), consisting of a transparent and a non-transparent part (due to the presence of non-dissolved theophylline crystals). These gel layers surrounded (solid) cores, which decreased in size with time. No clear correlation was found between: (i) the impact of the PEO polymer molecular weight on the drug release kinetics and (ii) the impact of the PEO polymer molecular weight on the dynamic changes in the thicknesses of the transparent and non-transparent gel layers, the dimensions of the (solid) cores, the dry mass (%), remaining PEO (%) or water content (%) of the different system portions. Interestingly, such a correlation was only observed with respect to the changes in the volume of the “(solid) cores + non-transparent gels” (dominated by the changes in their diameters).

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.

Hydroxypropyl methylcellulose (HPMC) is a frequently used matrix former for controlled release tablets. To adjust desired drug release kinetics, freely water-soluble lactose can be added. The aim of this study was to investigate the importance of the type of preparation technique of propranolol HCl loaded matrix tablets based on such HPMC:lactose blends. The tablets were prepared by: (i) direct compression of physical blends of drug, HPMC and lactose, (ii) direct compression of blends of the drug and co-processed HPMC:lactose (spray agglomerated), and (iii) via wet granulation. Interestingly, the co-processed HPMC:lactose particles provided better flowability and compactability than the physical HPMC:lactose blends, while the resulting water uptake kinetics and drug release rates were similar. Also wet granulation led to similar drug release kinetics. Thus, the use of co-processed HPMC:lactose can offer interesting technical advantages for the manufacturing of controlled release matrix tablets, while system performance remains unaltered.

Different types of poly(lactic-co-glycolic acid) (PLGA)- and poly(lactic acid) (PLA)-based implants for controlled dexamethasone release were prepared by hot melt extrusion (HME). The lactic acid:glycolic acid ratio was varied (50:50, 75:25, 100:0) as well as the drug loading (1–15%). Resomer RG 502H, RG 752H and R 202H (all with –COOH end groups) were studied. The implants were characterized before and after exposure to phosphate buffer pH 7.4 at 37 °C. Interestingly, in all cases polymer swelling seems to play an “orchestrating” role for drug release: At early time points, the amounts of water penetrating into the systems are limited (since the macromolecules are hydrophobic and highly entangled). Consequently, only small amounts of drug can dissolve and the dissolved drug molecules are not sufficiently mobile to diffuse out to a noteworthy extent (negligible dexamethasone release for up to 6 weeks). However, the water that is able to enter the implants at early time points cleaves the polyesters right from the beginning. Due to the newly generated –COOH end groups and decreased chain length, the macromolecules become more and more hydrophilic and less entangled. In addition, water-soluble polymer degradation products build up a steadily increasing osmotic pressure, attracting water into the system. Once a critical polymer molecular weight threshold range (around 8 kDa) is reached, substantial implant swelling starts: The systems' volume increases up to 600–1700% and the water contents exceeds 80–90% (partially approaching 100%). Under these fundamentally altered conditions, significant drug amounts can dissolve and the dissolved drug molecules are sufficiently mobile to diffuse out of the implants: Drug release sets on. In brief, polymer swelling “orchestrates” the involved mass transport phenomena: It enables drug release after a certain lag time by fundamentally changing the conditions for drug dissolution and diffusion. Note that in other types of implants, additional mass transport phenomena might be involved, e.g. no burst release was observed from the investigated, initially non-porous implants.

In pharmaceutical technology, lipids and polymers are considered pillar excipients for the fabrication of most dosage forms, irrespective of the administration route. They play various roles ranging from support vehicles to release rate modifiers, stabilizers, solubilizers, permeation enhancers and transfection agents. Focusing on selected applications, which were discussed at the Annual Scientific Meeting of the Gattefossé Foundation 2018, this manuscript recapitulates the fundamental roles of these two important classes of excipients, either employed alone or in combination, and provides insight on their functional properties in various types of drug formulations. Emphasis is placed on oral formulations for the administration of active pharmaceutical ingredients with low aqueous solubilities or poor permeation properties. Additionally, this review article covers the use of lipids and polymers in the design of colloidal injectable delivery systems, and as substrates in additive manufacturing technologies for the production of tailor-made dosage forms., International Journal of Pharmaceutics, 558, ISSN:0378-5173, ISSN:1873-3476, ISSN:0378 -5173

Different types of starches were used to prepare controlled release tablets loaded with diprophylline by direct compression. The impact of the natural origin of the starch, potential chemical modifications (e.g., cross-linking with phosphate or adipate, hydroxypropylation, acetylation to different degrees, partial hydrolysis) and type of pre-gelatinization process (laboratory scale with ethanol and oven drying versus industrial scale drum drying) on the resulting drug release kinetics were studied. Texture analysis of the hydrogels created upon exposure to the release medium, optical and scanning electron microscopy as well as X-ray powder diffraction measurements were used to better understand the observations. Also, a “quick test” using a texture analyzer to rapidly estimate the capacity of a specific starch type to control the resulting drug release rate was proposed. Two types of hydroxypropyl methylcellulose (HPMC K100 M and K100 LV) were studied for reasons of comparison. Interestingly, the “quick test” allowed to detect differences in the mechanical strength of the hydrogels formed upon contact with aqueous fluids, which correlated well with the observed drug release patterns from tablets when measured using a USP III (“Bio’-Dis”) apparatus at 30 rpm. However, diprophylline release was not very much affected by the investigated starch types when using a USP basket apparatus at 75 rpm. This can be attributed to the much lower mechanical stress experienced by the hydrogels under these conditions. Furthermore, caution must be paid when studying starch types, which are pre-gelatinized at the laboratory scale using ethanol precipitation and oven drying. The obtained starch granules can have significantly different key properties compared to granules obtained by industrial scale drum drying, resulting in substantially different drug release patterns.

High-resolution X-ray microtomography was used to get deeper insight into the underlying mass transport mechanisms controlling drug release from coated pellets. Sugar starter cores were layered with propranolol HCl and subsequently coated with Kollicoat SR, plasticized with 10% TEC. Importantly, synchrotron X-ray computed microtomography (SR-μCT) allowed direct, non-invasive monitoring of crack formation in the film coatings upon exposure to the release medium. Propranolol HCl, as well as very small sugar particles from the pellets' core, were expulsed through these cracks into the surrounding bulk fluid. Interestingly, SR-μCT also revealed the existence of numerous tiny, air-filled pores (varying in size and shape) in the pellet cores before exposure to the release medium. Upon water penetration into the system, the contents of the pellet cores became semi-solid/liquid. Consequently, the air-pockets became mobile and fused together. They steadily increased in size (and decreased in number). Importantly, “big” air bubbles were often located in close vicinity of a crack within the film coating. Thus, they play a potentially crucial role for the control of drug release from coated pellets.

Trauma and orthopedic surgery can cause infections as any open surgical procedures. Such complications occur in only1 to 5% of the cases, but the treatment is rather complicated due to bacterial biofilm formation and limited drug access to the site of infection upon systemic administration. An interesting strategy to overcome this type of complications is to prevent bacterial proliferation and biofilm formation via the local and controlled release of antibiotic drugs from the implant itself. Obviously, the incorporation of the drug into the implant should not affect the latter's biological and mechanical properties. In this context, we optimized the preparation process for gentamicin-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles, which can be incorporated in the macropores of calcium phosphate-based bone substitutes. Microparticles were prepared using a double emulsion solvent extraction/evaporation technique. The processing parameters were optimized in order to provide an average microparticle size of about 60μm, allowing for incorporation inside the macropores (100μm) of the hydroxyapatite scaffold. Gentamicin-loaded PLGA microparticles showed a sustained release for 25-30days and a rapid antibacterial activity due to a burst effect, the extent of which was controlled by the initial loading of the microparticles. SEM pictures revealed a highly porous microparticle structure, which can help to reduce the micro environmental pH drop and autocatalytic effects. The biological evaluation showed the cytocompatibility and non-hemolytic property of the microparticles, and the antibacterial activity against Staphylococcus aureus under the given conditions.

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.

Silicone-based drug delivery systems offer a great potential to improve the therapeutic efficacy and safety of a large variety of medical treatments, e.g. allowing for local long-term delivery of active agents to the inner ear. Different formulation parameters can be varied to adjust desired drug release kinetics. However, often only qualitative information is available on their effects, and product optimization is cumbersome. The aim of this study was to provide a quantitative analysis, allowing also for theoretical predictions of the impact of the device design on system performance. Dexamethasone was incorporated into thin films based on different types of silicones (e.g. varying in the type of side chains and contents of amorphous silica), optionally containing different types and amounts of poly(ethylene glycol) (PEG) (5% or 10%). Furthermore, the initial drug content was altered (from 10% to 50%). In most cases, an analytical solution of Fick's second law could be used to describe the resulting drug release kinetics from the films and to determine the respective "apparent" diffusion coefficient of the drug (which varied from 2×10(-14) to 2×10(-12)cm(2)/s, depending on the system's composition). Thus, the impact of the investigated formulation parameters on drug mobility in the polymeric matrices could be quantitatively described. Importantly, the knowledge of the "apparent" drug diffusivity can be used to theoretically predict the resulting release kinetics from dosage forms of arbitrary size and shape. For instance, dexamethasone release was theoretically predicted from cylindrical extrudates based on a selection of different silicone types. Interestingly, these predictions could be confirmed by independent experiments. Hence, this type of quantitative analysis can replace time-consuming and cost-intensive series of trial-and-error experiments during product optimization. This is particularly helpful, if long-term drug release (e.g., during several weeks, months or years) is targeted.

The development of novel therapeutics with improved efficacy implies increasing complexity of drug delivery systems, which in turn require advanced methods for their analytical characterization. Among these systems, pellets represent upcoming carrier systems, which show several advantages like simplified dosing and improved compliance among children and the aged population. However, rational development of such systems is hampered by the lack of non-destructive, chemically selective analytical insight into compound distribution and drug release mechanisms. The aim of this study was to evaluate confocal Raman microscopy (CRM) for investigation of coated drug-loaded pellets based on visualization of compound distribution and elucidation of drug release mechanisms. Three complementary approaches were applied for pellet characterization: analysis of cross sections after bisectioning, non-invasive visualization of the pellet surface, and virtual cross sectioning in x–z direction. As the surface of such pellets is structured, a complementary approach of optical topography and CRM was applied for three-dimensional analysis. Based on the individual Raman peak patterns, the drug and excipients forming the matrix of the pellets and the film coating were successfully visualized with high spatial resolution, verifying homogeneous drug distribution and intact polymer coating of the pellet. Further, analysis of the pellets after certain time intervals during drug release testing revealed pore formation in the polymer coating facilitating drug release and preceding drug depletion in the pellets matrix. CRM represents an upcoming technique for analytical characterization of carrier systems and elucidation of their complex drug release mechanisms, thus supporting rational development of novel therapeutics. Copyright © 2016 John Wiley & Sons, Ltd.

It has recently been reported that system swelling is likely to control the onset of the third release phase from ketoprofen -loaded PLGA microparticles: However, yet it is unclear whether this type of release mechanism is also valid for other types of drugs. In this study, PLGA microparticles were loaded with different amounts of the free base prilocaine, keeping the microparticle size constant. The systems were characterized using GPC, DSC, SEM, X-ray powder diffraction, drug release measurements and the monitoring of single microparticle swelling. At lower drug loadings, tri-phasic release patterns were observed: An initial burst was followed by a period with an about constant release rate, which was followed by a third, again rapid release phase. Interestingly, the beginning of this final rapid drug release phase coincided with the onset of substantial microparticle swelling. GPC analysis revealed that the PLGA molecular weight was about 18–19 k Da at these “onset time points”. Thus, it seems that as soon as a critical polymer molecular weight is reached, important amounts of water penetrate into the system, leading to significantly increased polymer and drug mobility. Hence, microparticle swelling seems to cause the onset of the final release phase of different types of drugs.

Polymeric fenofibrate-loaded films and particles aiming at improved dissolution of this poorly water-soluble drug were prepared by solvent evaporation or co-grinding. HPMC, PVP and PEG of various molecular weights were studied. In the case of HPMC, thin films were obtained when using the solvent evaporation method, whereas in all other cases particles were obtained. Interestingly, not only the type of polymer, but also the preparation method had a substantial impact on system performance and this in a not straightforward manner: For HPMC and PVP, solvent evaporation was much more efficient than co-grinding, whereas the opposite was observed with PEG. Fenofibrate was molecularly dispersed in HPMC and PVP, whereas it was partially dissolved and partially dispersed in the form of small crystals in PEG, irrespective of the type of preparation technique. Differences in the particle size could explain why drug release was faster from PVP-based systems prepared by solvent evaporation compared to co-grinding, and why the opposite was true in the case of PEG. For HPMC, differences in system homogeneity could explain the effects of the type of preparation method. Importantly, the drug dissolution rate and extent could be substantially increased, while assuring stability during at least 3 months open storage.

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.

International audience; Control of infection and inflammation is crucial for the success of periodontal treatment. In this study, in-situ forming implants (ISFI) loaded with chlorhexidine dihydrochloride (CHX) and ibuprofen (IBU) were developed and tested to optimize periodontal treatment outcomes. Release profiles were promising. Exposure to 1.5% and 5.3% CHX-IBU loaded ISFI's release media decreased significantly the P. gingivalis growth up to 20-fold and 35-fold, respectively, after 48 h (p < 0.05). The metabolic activity assay of gingival epithelial cells (EC) demonstrated 1.5% CHX-IBU-loaded ISFI to be non-toxic, therefore, it was selected for further experimentation. Furthermore, significant down-regulation of TNF-α release (34% at 6 h and 43% at 24 h, p < 0.05) in P. gingivalis lipopolysaccharide (Pg-LPS) stimulated EC exposed to 1.5% CHX-IBU ISFI release medium was demonstrated by ELISA. In vivo, 1.5% CHX-IBU ISFI was injected into the periodontal pocket in an experimental periodontitis mouse model and the reduction in inflammation and improvement in periodontal wound healing was evaluated through inflammatory cell scoring and histomorphometry at 7- and 15-days post-treatment. The results indicate that CHX-IBU loaded ISFI could be efficient as adjuvant to periodontal therapy for the control of infection and inflammation. Moreover, other (e.g., pro-regenerative) drugs could be incorporated into ISFI to further improve periodontal treatment outcomes.

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.

International audience; This study aims to investigate the polymorphism, physical stability, and amorphization possibilities of dexamethasone (DEX) drug. Milling was found to be an advantageous mean to prepare amorphous DEX nonchemically degraded. It appears to be a very useful process that allowed generating crystalline polymorphic transformation, either from the milling induced amorphous sample or from a mechanically damaged polymorphic form. The paper illustrates the interest of milling as a complementary tool to screen crystal polymorphism and to determine the relative stability of polymorphs when the decision is difficult. Physical characterizations were mainly carried out using X-ray diffraction and differential scanning calorimetry.