Martin Körber

PLGA Erosion: Solubility- or Diffusion-Controlled?

ABSTRACTPurposeTo calculate the degradation time-dependent formation of water-soluble PLGA oligomers and to evaluate the relation between calculated oligomer formation and actual erosion of a PLGA-based delivery system. A proper model of the erosion process would be expected to facilitate forecasting of drug release profiles from PLGA matrices due to the close relationship of erosional mass loss and drug release described in the literature.MethodsThe molecular weight distribution (MWD), degradation and erosion behaviour of PLGA were characterized by gel permeation chromatography.ResultsPLGA was characterized by a lognormal distribution of mass fractions of individual molecular weights. Implementation of the pseudo-first-order reaction kinetics into the MWD function facilitated calculating the formation of water-soluble oligomers during degradation. The calculated soluble oligomer formation agreed excellently with measured erosional mass loss of a PLGA matrix in aqueous buffer, which suggested that the bulk erosion process was solely controlled by the kinetic of the formation of soluble oligomers and thus solubility-controlled and not diffusion-limited as conventionally assumed.ConclusionThe accurately calculated formation of soluble PLGA oligomers was in excellent agreement with the actual erosional mass loss of a PLGA matrix, suggesting that bulk erosion of PLGA represents a degradation-controlled dissolution process.

Development of an in situ forming PLGA drug delivery system I. Characterization of a non-aqueous protein precipitation.

The incorporation of the model protein hen egg white lysozyme into liquid in situ forming poly(lactide-co-glycolide) (PLGA) implant or microparticle formulations was investigated. Ternary solvent blends of dimethyl sulfoxide (DMSO), ethyl acetate and water were used to adjust the protein solubility in order to facilitate the incorporation of either dispersed or dissolved protein into the polymer solution. Lysozyme formed large gel particles when dispersed directly in the polymer solution. These formulations had a pronounced initial release. Non-aqueous precipitation of lysozyme from solutions in DMSO with ethyl acetate led to a reversible aggregation without loss in biological activity. Lysozyme could be incorporated in a finely dispersed state through an in situ precipitation by non-solvent or polymer addition. Non-aqueous precipitation could thus be utilized to manufacture biodegradable in situ forming drug delivery systems containing homogeneously distributed and bioactive protein.

Protein release from poly(lactide-co-glycolide) implants prepared by hot-melt extrusion: Thioester formation as a reason for incomplete release

The aim of this study was to characterize the protein release from PLGA-based implants prepared by hot-melt extrusion with special emphasis on identifying reasons for incomplete release. Biodegradable PLGA-implants loaded with BSA were prepared with a syringe-die extrusion device. A burst-free release was achieved up to 25% BSA loading by milling the protein prior to extrusion. The release was incomplete at 70% at loadings below the percolation threshold of the protein; higher protein loadings increased the release to 97%. However, an insoluble implant mass remained for over 180 days, which was attributed to the acylation of BSA by PLGA oligomers via a thioester bond. The incomplete protein release due to the formation of this covalent bond was overcome when increasing the porosity of the implant, which effectively reduced the contact between BSA and PLGA oligomers. Accordingly, melt-extrusion facilitated incorporating high loadings of BSA into burst-free biodegradable implants. Additionally, it enhanced complete protein release by a process- or formulation controlled increase of the implant porosity.

Direct compression of cushion-layered ethyl cellulose-coated extended release pellets into rapidly disintegrating tablets without changes in the release profile.

The aim of this study was to develop and optimize a segregation-free ethyl cellulose-coated extended release multiparticulate formulation to be compressed into tablets without affecting the drug release. Standard tableting excipients (e.g., microcrystalline cellulose, lactose or sorbitol) were layered onto ethyl cellulose-coated propranolol hydrochloride pellets to form a cushion layer in order to eliminate segregation problems normally resulting from particle size difference between coated pellets and excipient powders and second to protect the integrity of the brittle ethyl cellulose coating during compression. The disintegration behavior of the tablets depended strongly on the composition of the cushion layer. Rapid tablet disintegration was obtained with microcrystalline cellulose and the disintegrant sodium croscarmellose. However, the drug release from these cushion-layered pellets still increased upon compression. Incorporation of a glidant into the cushion layer or between the cushion layer and the ethyl cellulose coating reduced the compression effect on drug release markedly. Glidant-containing formulations showed a delayed deformation and damage of the ethyl cellulose-coated pellet upon mechanical stress. In summary, cushion layer based on microcrystalline cellulose facilitated segregation-free compression of a highly compression-sensitive extended release ethyl cellulose-coated pellets into fast-disintegrating and hard tablets without compromising the release properties of the multiparticulates. Directly compressible cushion-layered pellets protected the pellet coating significantly better from damages during tabletting when compared to the conventional compression of blends of coated pellets and excipient powders.

Interdependency of protein-release completeness and polymer degradation in PLGA-based implants.

Release of BSA (model protein) from hot-melt extruded poly(lactide-co-glycolide) (PLGA)-based implants was incomplete. A residual mass of covalent BSA-PLGA adducts was still present after 6 months. The objective of this study was to increase the completeness of BSA release. BSA reduced the PLGA degradation and erosion rate as well as the extent of erosion. An increased uptake of release medium in the presence of BSA in addition to the early outflux of PLGA oligomers resulted in a reduction of the matrix acidity and thus reduction of autocatalysis effects. PLGA mass loss was incomplete at 60% and 80% for 10% and 25% BSA-containing implants. The extent of PLGA mass loss was correlated with the total releasable protein. The same release was obtained from implants prepared with pre-degraded PLGA suggesting that the induction phase did not affect the release completeness. Thus, the focus was on the erosion phase to enhance outflux of soluble oligomers. BSA release completeness increased by increasing the porosity of the implants at the onset of erosion phase. This could be obtained with a higher initial porosity, formation of porosity upon higher diffusional release and/or incorporation of pore-formers/plasticizers. Accordingly, the BSA release completeness could be improved by enhancing the outflux of soluble PLGA degradation products.

Effect of unconventional curing conditions and storage on pellets coated with Aquacoat ECD

Purpose: Purpose of this study was to develop storage stable pellets coated with the aqueous ethylcellulose dispersion Aquacoat ECD. Methods: The influence of accelerated curing/storage conditions on the release behavior of Aquacoat/HPMC-coated drug pellets were investigated as a function of various formulations (sealing, plasticizer content, and pore-former type/amount) and process parameters (process humidity, thermal curing, and organic processing). Results: Conventionally cured Aquacoat/hydroxypropyl methylcellulose-coated pellets were storage stable at ambient conditions and 25°C/60% relative humidity (RH) but showed a decreasing drug release at 40°C/75% RH, which is a required test condition according to ICH guidelines. Conclusion: Only organic processing of dried Aquacoat or unconventionally harsh curing conditions (60°C/75% RH or 80°C) improved the storage stability of Aquacoat-coated pellets at accelerated conditions.

Predictability of drug release from water-insoluble polymeric matrix tablets

The purpose of this study was to extend the predictability of an established solution of Ficks second law of diffusion with formulation-relevant parameters and including percolation theory. Kollidon SR (polyvinyl acetate/polyvinylpyrrolidone, 80/20 w/w) matrix tablets with various porosities (10-30% v/v) containing model drugs with different solubilities (Cs=10-170 mg/ml) and in different amounts (A=10-90% w/w) were prepared by direct compression and characterized by drug release and mass loss studies. Drug release was fitted to Ficks second law to obtain the apparent diffusion coefficient. Its changes were correlated with the total porosity of the matrix and the solubility of the drug. The apparent diffusion coefficient was best described by a cumulative normal distribution over the range of total porosities. The mean of the distribution coincided with the polymer percolation threshold, and the minimum and maximum of the distribution were represented by the diffusion coefficient in pore-free polymer and in aqueous medium, respectively. The derived model was verified, and the applicability further extended to a drug solubility range of 10-1000 mg/ml. The developed mathematical model accurately describes and predicts drug release from Kollidon SR matrix tablets. It can efficiently reduce experimental trials during formulation development.

Enteric polymers as acidifiers for the pH-independent sustained delivery of a weakly basic drug salt from coated pellets

Weakly basic drugs and their salts exhibit a decrease in aqueous solubility at higher pH, which can result in pH-dependent or even incomplete release of these drugs from extended release formulations. The objective of this study was to evaluate strategies to set-off the very strong pH-dependent solubility (solubility: 80 mg/ml at pH 2 and 0.02 mg/ml at pH 7.5, factor 4000) of a mesylate salt of weakly basic model drug (pK(a) 6.5), in order to obtain pH-independent extended drug release. Three approaches for pH-independent release were investigated: (1) organic acid addition in the core, (2) enteric polymer addition to the extended release coating and (3) an enteric polymer subcoating below the extended release coating. The layering of aspartic acid onto drug cores as well as the coating of drug cores with an ethylcellulose/Eudragit L (enteric polymer) blend were not effective to avoid the formation of the free base at pH 7.5 and thus failed to significantly improve the completeness of the release compared to standard ethylcellulose/hydroxypropyl cellulose (EC/HPC)-coated drug pellets. Interestingly, the incorporation of an enteric polymer layer underneath the EC/HPC coating decreased the free base formation at pH 7.5 and thus resulted in a more complete release of up to 90% of the drug loading over 18 h. The release enhancing effect was attributed to an extended acidification through the enteric polymer layer. Flexible release patterns with approximately pH-independent characteristics were successfully achieved.

Improving release completeness from PLGA-based implants for the acid-labile model protein ovalbumin

The objectives of this study were to assess the feasibility of hot melt extrusion (HME) for the preparation of PLGA-based ovalbumin-loaded implants as well as to characterize and improve protein release from the implants. Ovalbumin (OVA) was stable during extrusion, which was attributed to a protective effect of the biodegradable matrix. OVA release was characterized by a low burst, a slow release up to day 21, which plateaued thereafter resulting in incomplete release for all evaluated protein loadings. Release incompleteness was accompanied by the formation of an insoluble residual mass. Further characterization of this mass indicated that it consisted of non-covalent protein aggregates and polymer, where ovalbumin was ionically bound as the pH inside the degrading matrix decreased below the pI of the protein. Although higher protein release was obtained with the inclusion of weak bases because of their neutralizing effect, OVA aggregation and release incompleteness were not fully avoided. With the use of shellac, a well-known enteric and biocompatible polymer, as protective excipient, a distinct late release phase occurred and release completeness was increased to more than 75% cumulative release. Shellac apparently protected the protein against the acidic microclimate due to its low solubility at low pH. Protected OVA was thus released once the pH increased due to a declining PLGA-oligomer formation. The result was a triphasic release profile consisting of an initial burst, a slow diffusion phase over about 7 weeks, and an erosion-controlled dissolution phase over the next 3 weeks. An acid-labile protein like OVA was thus feasibly protected from interactions with PLGA and its degradation products, resulting in a controlled delivery of more than 85% of the original payload.

Impact of change of matrix crystallinity and polymorphism on ovalbumin release from lipid-based implants

&NA; The objectives of this study were to prepare lipid‐based implants by hot melt extrusion (HME) for the prolonged release of ovalbumin (OVA), and to relate protein release to crystallinity and polymorphic changes of the lipid matrix. Two lipids, glycerol tristearate and hydrogenated palm oil, with different composition and degree of crystallinity were studied. Solid OVA was dispersed within the lipid matrixes, which preserved its stability during extrusion. This was partially attributed to a protective effect of the lipidic matrix. The incorporation of OVA decreased the mechanical strength of the implants prepared with the more crystalline matrix, glycerol tristearate, whereas it remained comparable for the hydrogenated palm oil because of stronger physical and non‐covalent interactions between the protein and this lipid. This was also the reason for the faster release of OVA from the glycerol tristearate matrix when compared to the hydrogenated palm oil (8 vs. 28 weeks). Curing induced and increased crystallinity, and changes in the release rate, especially for the more crystalline matrix. In this case, both an increase and a decrease in release, were observed depending on the tempering condition. Curing at higher temperatures induced a melt‐mediated crystallization and solid state transformation of the glycerol tristearate matrix and led to rearrangements of the inner structure with the formation of larger pores, which accelerated the release. In contrast, changes in the hydrogenated palm oil under the same curing conditions were less noticeable leading to a more robust formulation, because of less polymorphic changes over time. This study helps to understand the effect of lipid matrix composition and crystallinity degree on the performance of protein‐loaded implants, and to establish criteria for the selection of a lipid carrier depending on the release profile desired. Graphical abstract Figure. No caption available.