Rob Steendam

Effect of molecular weight and glass transition on relaxation and release behaviour of poly(DL-lactic acid) tablets

Different molecular weight grades of poly(DL-lactic acid) were applied as release controlling excipients in tablets for oral drug administration. The role of molecular weight and glass transition in the mechanism of water-induced volume expansion and drug release of PDLA tablets was investigated. Modulated differential scanning calorimetry (MDSC) was used to determine the glass transition temperature of both dry and hydrated PDLA samples. The absorption rate and total amounts of sorbed water by the polymer were determined by dynamic vapour sorption (DVS). Expansion behaviour of PDLA tablets was measured using thermal mechanical analysis (TMA). At 95% relative humidity all molecular weight grades of PDLA sorbed 1.1-1.3% w/w water, as was determined with DVS. MDSC showed glass transition temperature reductions of 10-11 degrees C for all molecular weight grades of PDLA in water. Volume expansion studies using TMA showed that the molecular relaxation time and equilibrium porosity of the tablets increased with molecular weight. The mean relaxation time increased exponentially with the temperature interval T(g)-T. The onset temperature of shape recovery of hydrated tablets was approximately 8 degrees C lower than for dry samples. Drug release was only slightly affected by molecular weight. It is concluded that volume expansion of compressed PDLA tablets is related to the glass transition behaviour, originates from water-induced and thermally stimulated shape memory behaviour and is therefore highly dependent on the molecular weight of PDLA.

Plasticisation of amylodextrin by moisture. Consequences for compaction behaviour and tablet properties

PURPOSE Amylodextrin, a starch-based controlled release excipient, spontaneously absorbs moisture during storage. The aim of this study was to investigate plasticisation of amylodextrin by moisture and its effect on compaction and tablet characteristics. METHODS The glass transition temperature (T(g)) of amylodextrin powders with moisture fractions (x(w)) 0.070<x(w)<0.40 was studied by conventional and modulated DSC. Elastic modulus and yield stress were determined from compressive stress-strain experiments. Compaction behaviour was studied at 3 and 300 mm/s using a compaction simulator. RESULTS The T(g) of amylodextrin-water blends showed a smooth reduction with increasing x(w), equalling room temperature at x(w)=0.19. Experimentally obtained T(g) values were close to temperatures as predicted by the Gordon-Taylor/Kelley-Bueche model and the modified Couchman-Karasz model. The elastic modulus decreased steeply between x(w)=0.17 and 0.23. Compaction experiments showed that moisture facilitated consolidation due to increasing powder compressibility and reduced compact relaxation. However, at x(w)=0.23, compressibility was reduced and relaxation significantly higher due to the rubbery character of this powder. Consequently, the lowest tablet porosities were obtained around x(w)=0.15. Although decreasing porosities enhanced tablet strengths, the maximum obtainable tablet strengths decreased with moisture due to reduced particle bonding and lowering of the elastic modulus. CONCLUSION Moisture largely affects the visco-elastic and compaction characteristics of amylodextrin. Hence, control over moisture content is essential to produce tablets with reproducible porosity, strength and dissolution characteristics.

Low temperature extruded implants based on novel hydrophilic multiblock copolymer for long-term protein delivery

Parenteral protein delivery requires preservation of the integrity of proteins and control over the release kinetics. In order to preserve the integrity, parenteral protein delivery formulations typically need to be processed at low temperatures. Therefore, we synthesized a novel low melting biodegradable hydrophilic multiblock copolymer composed of poly (ethylene glycol) and poly (ε-caprolactone) to allow extrusion at relatively low temperatures. We investigated the extrusion characteristics of this polymer and explored a strategy how to control the release of the model protein lysozyme from small diameter extruded implants. It was found that the polymer could be well extruded at temperatures as low as 55 °C. Moreover, lysozyme remained active both during extrusion as well as during release. Lysozyme release kinetics could be tailored by the co-incorporation of an oligosaccharide, inulin, which functions as a pore-forming excipient. It was concluded that this hydrophilic multiblock copolymer has promising characteristics for the preparation by melt extrusion of protein delivery implants with a release profile that is sustained over a period of more than 7 months.

Sunitinib microspheres based on [PDLLA-PEG-PDLLA]-b-PLLA multi-block copolymers for ocular drug delivery

Sunitinib is a multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks several angiogenesis related pathways. The aim of this study was to develop sunitinib-loaded polymeric microspheres that can be used as intravitreal formulation for the treatment of ocular diseases. A series of novel multi-block copolymers composed of amorphous blocks of poly-(D,L-lactide) (PDLLA) and polyethylene glycol (PEG) and of semi-crystalline poly-(L-lactide) (PLLA) blocks were synthesized. Sunitinib-loaded microspheres were prepared by a single emulsion method using dichloromethane as volatile solvent and DMSO as co-solvent. SEM images showed that the prepared microspheres (∼ 30 μm) were spherical with a non-porous surface. Sunitinib-loaded microspheres were studied for their degradation and in-vitro release behavior. It was found that increasing the percentage of amorphous soft blocks from 10% to 30% accelerated the degradation of the multi-block copolymers. Sunitinib microspheres released their cargo for a period of at least 210 days by a combination of diffusion and polymer erosion. The initial burst (release in 24h) and release rate could be tailored by controlling the PEG-content of the multi-block copolymers. Sunitinib-loaded microspheres suppressed angiogenesis in a chicken chorioallantoic membrane (CAM) assay. These microspheres therefore hold promise for long-term suppression of ocular neovascularization.

Tailored protein release from biodegradable poly(ε-caprolactone-PEG)- b-poly(ε-caprolactone) multiblock-copolymer implants

In this study, the in vitro release of proteins from novel, biodegradable phase-separated poly(ε-caprolactone-PEG)-block-poly(ε-caprolactone), [PCL-PEG]-b-[PCL]) multiblock copolymers with different block ratios and with a low melting temperature (49-55°C) was studied. The effect of block ratio and PEG content of the polymers (i.e. 22.5, 37.5 and 52.5 wt%) as well as the effect of protein molecular weight (1.2, 5.8, 14, 29 and 66 kDa being goserelin, insulin, lysozyme, carbonic anhydrase and albumin, respectively) on protein release was investigated. Proteins were spray-dried with inulin as stabilizer to obtain a powder of uniform particle size. Spray-dried inulin-stabilized proteins were incorporated into polymeric implants by hot melt extrusion. All incorporated proteins fully preserved their structural integrity as determined after extraction of these proteins from the polymeric implants. In general, it was found that the release rate of the protein increased with decreasing molecular weight of the protein and with increasing the PEG content of the polymer. Swelling and degradation rate of the copolymer increased with increasing PEG content. Hence, release of proteins of various molecular weights from [PCL-PEG]-b-[PCL] multi-block copolymers can be tailored by varying the PEG content of the polymer.

Local therapeutic efficacy with reduced systemic side effects by rapamycin-loaded subcapsular microspheres

Kidney injury triggers fibrosis, the final common pathway of chronic kidney disease (CKD). The increase of CKD prevalence worldwide urgently calls for new therapies. Available systemic treatment such as rapamycin are associated with serious side effects. To study the potential of local antifibrotic therapy, we administered rapamycin-loaded microspheres under the kidney capsule of ureter-obstructed rats and assessed the local antifibrotic effects and systemic side effects of rapamycin. After 7 days, microsphere depots were easily identifiable under the kidney capsule. Both systemic and local rapamycin treatment reduced intrarenal mTOR activity, myofibroblast accumulation, expression of fibrotic genes, and T-lymphocyte infiltration. Upon local treatment, inhibition of mTOR activity and reduction of myofibroblast accumulation were limited to the immediate vicinity of the subcapsular pocket, while reduction of T-cell infiltration was widespread. In contrast to systemically administered rapamycin, local treatment did not induce off target effects such as weight loss. Thus subcapsular delivery of rapamycin-loaded microspheres successfully inhibited local fibrotic response in UUO with less systemic effects. Therapeutic effect of released rapamycin was most prominent in close vicinity to the implanted microspheres.

Poly(DL-lactic acid) as a direct compression excipient in controlled release tablets - Part I. Compaction behaviour and release characteristics of poly(DL-lactic acid) matrix tablets

High-molecular weight poly(DL-lactic acid) (PDLA, M-v 85000) was applied as a direct compression excipient in controlled release tablets. PDLA powders with good flowing properties were obtained by milling pre-cooled PDLA granules. Apparent yield pressure values ranged from 44 to 71 MPa for tabletting speeds of 0.033 and 300 mm/s, respectively, pointing to a high ductility and limited strain rate sensitivity. Tablets with good mechanical strength (tensile strength 2.5-3.7 MPa) were prepared at different compaction speeds. Dissolution experiments with different drugs showed that PDLA exhibited good sustained release properties. Initial tablet porosity, lubrication with magnesium stearate and pH of the dissolution medium hardly affected the release rate of the incorporated drug. Drug loads, however, markedly affected the release rate. For drug loads between 20 and 50% w/w, a constant fractional release rate was found. Upon further decreasing of the drug load, the release rate was found to increase. This remarkable finding was explained by the rapid and large increase of the pore volume of the tablets. The results show the unique properties of PDLA and its suitability to be applied as a direct compression and release controlling excipient in matrix tablets for oral drug administration

Protein release from water-swellable poly(d,l-lactide-PEG)-b-poly(ϵ-caprolactone) implants

In this study, water-swellable multiblock copolymers composed of semi-crystalline poly(ϵ-caprolactone) [PCL] blocks and amorphous blocks consisting of poly(D,L-lactide) (PDLLA) and poly(ethylene glycol) (PEG) [PDLLA-PEG] were synthesized. The block ratio of these [PDLLA-PEG]-b-[PCL] multiblock copolymers was varied and the degradation of implants prepared of these polymers by hot melt extrusion (HME) was compared with implants prepared of [PCL-PEG]-b-[PCL], a copolymer which has been described previously (Stanković et al., 2014). It was shown that the initial degradation rate of the [PDLLA-PEG]-b-[PCL] multiblock copolymers increased with increasing the content of amorphous [PDLLA-PEG] block and that the degradation rate of these multiblock copolymers was faster than that of the [PCL-PEG]-b-[PCL] multiblock copolymers due to rapid degradation of the [PDLLA-PEG] block. Furthermore, the release of the model proteins lysozyme and bovine serum albumin from polymer implants prepared by HME was studied. It was found that the protein release from [PDLLA-PEG]-b-[PCL] copolymers was incomplete, which is not acceptable for any application of these polymers. Besides, [PCL-PEG]-b-[PCL] copolymers showed slow and continuous release. We hypothesize that the incomplete release is explained by an irreversible interaction between the proteins and polymer degradation products or by entrapment of the protein in the hydrophobic and non-swellable polymer matrix that was left after degradation and loss of the hydrophilic [PDLLA-PEG] blocks from the degrading polymer.

Nanomechanical properties of multi-block copolymer microspheres for drug delivery applications

Biodegradable polymeric microspheres are interesting drug delivery vehicles for site-specific sustained release of drugs used in treatment of osteoarthritis. We study the nano-mechanical properties of microspheres composed of hydrophilic multi-block copolymers, because the release profile of the microspheres may be dependent on the mechanical interactions between the host tissues and the microspheres that aim to incorporate between the cartilage surfaces. Three different sizes of monodisperse microspheres, namely 5, 15, and 30μm, were tested in both dry and hydrated (swollen) states. Atomic force microscopy was used for measuring nanoindentation-based force-displacement curves that were later used for calculating the Young׳s moduli using the Hertz׳s contact theory. For every microsphere size and condition, the measurements were repeated 400-500 times at different surface locations and the histograms of the Young׳s modulus were plotted. The mean Young׳s modulus of 5, 15, and 30μm microspheres were respectively 56.1±71.1 (mean±SD), 94.6±103.4, and 57.6±58.6MPa under dry conditions and 226.4±54.2, 334.5±128.7, and 342.5±136.8kPa in the swollen state. The histograms were not represented well by the average Young׳s modulus and showed three distinct peaks in the dry state and one distinct peak in the swollen state. The peaks under dry conditions are associated with the different parts of the co-polymeric material at the nano-scale. The measured mechanical properties of swollen microspheres are within the range of the nano-scale properties of cartilage, which could favor integration of the microspheres with the host tissue.

Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFβ-receptor in the fibrotic kidney

Injectable sustained release drug delivery systems are an attractive alternative for the intravenous delivery of therapeutic proteins. In particular, for chronic diseases such as fibrosis, this approach could improve therapy by reducing the administration frequency while avoiding large variations in plasma levels. In fibrotic tissues the platelet-derived growth factor receptor beta (PDGFβR) is highly upregulated, which provides a target for site-specific delivery of drugs. Our aim was to develop an injectable sustained release formulation for the subcutaneous delivery of the PDGFβR-targeted drug carrier protein pPB-HSA, which is composed of multiple PDGFβR-recognizing moieties (pPB) attached to human serum albumin (HSA). We used blends of biodegradable multi-block copolymers with different swelling degree to optimize the release rate using the model protein HSA from microspheres produced via a water-in-oil-in-water double emulsion evaporation process. The optimized formulation containing pPB-HSA, showed complete release in vitro within 14days. After subcutaneous administration to mice suffering from renal fibrosis pPB-HSA was released from the microspheres and distributed into plasma for at least 7days after administration. Furthermore, we demonstrated an enhanced accumulation of pPB-HSA in the fibrotic kidney. Altogether, we show that subcutaneously administered polymeric microspheres present a suitable sustained release drug delivery system for the controlled systemic delivery for proteins such as pPB-HSA.