Quantification of porogen effect on the drug release from single- and multi-layered ethylcellulose coated pellets containing single or combined drugs.

The aim of this work was to develop a mathematical model to estimate the drug release from a conventional single-compartment reservoir pellet and extend its applicability to multi-compartment reservoir pellets. Conventional pellets were prepared by layering the drug onto starter-core then applying various ethylcellulose/HPC coatings for drug release control. Multi-layered pellets comprised a first drug layer of propranolol HCl (D1) followed by a first controlled release coating (C1) and consecutively a second drug layer of carbamazepine or caffeine (D2) and then a second controlled-release coating (C2). Drug release from single- and multi-compartment pellets generally increased with an increase of the water-soluble HPC in the coatings. The response described a sigmoidal curve, which agreed with a cumulative normal distribution function. The developed mathematical model facilitated quantification of the drug release of pellets as a function of the porogen content and the coating level. Additionally, the model was applied successfully in multi-compartment pellets to calculate theses effects on the release of drugs with a broad range of aqueous solubility.

Evaluation of Hydrogenated Soybean Phosphatidylcholine Matrices Prepared by Hot Melt Extrusion for Oral Controlled Delivery of Water-Soluble Drugs.

The aims of this study were to prepare hydrogenated soybean phosphatidylcholine (HSPC) matrices by hot melt extrusion and to evaluate resulting matrix potential to extend drug release in regard to drug loading and solubility for oral drug delivery of water-soluble drugs. The liquid crystalline nature of HSPC powder allowed its extrusion at 120°C, which was below its capillary melting point. Model drugs with a wide range of water solubilities (8, 20 and 240 mg/mL) and melting temperatures (160-270°C) were used. Extrudates with up to 70% drug loading were prepared at temperatures below the drugs' melting points. The original crystalline state of the drugs remained unchanged through the process as confirmed by XRPD and hot-stage microscopy. The time to achieve 80% release (t80) from extrudates with 50% drug loading was 3, 8 and 18 h for diprophylline, caffeine and theophylline, respectively. The effect of matrix preparation method (extrusion vs. compression) on drug release was evaluated. For non-eroding formulations, the drug release retarding properties of the HSPC matrix were mostly not influenced by the preparation method. However, with increasing drug loadings, compressed tablets eroded significantly more than extruded matrices, resulting in 2 to 11 times faster drug release. There were no signs of erosion observed in extrudates with different drugs up to 70% loadings. The mechanical robustness of HSPC extrudates was attributed to the formation of a skin-core structure and was identified as the main reason for the drug release controlling potential of the HSPC matrices produced by hot melt extrusion.

Resonance Eigenfunction Hypothesis for Chaotic Systems.

A hypothesis about the average phase-space distribution of resonance eigenfunctions in chaotic systems with escape through an opening is proposed. Eigenfunctions with decay rate γ are described by a classical measure that (i) is conditionally invariant with classical decay rate γ and (ii) is uniformly distributed on sets with the same temporal distance to the quantum resolved chaotic saddle. This explains the localization of fast-decaying resonance eigenfunctions classically. It is found to occur in the phase-space region having the largest distance to the chaotic saddle. We discuss the dependence on the decay rate γ and the semiclassical limit. The hypothesis is numerically demonstrated for the standard map.

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

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.

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.

Saturated phosphatidylcholine as matrix former for oral extended release dosage forms.

The aim of this study was to evaluate the suitability of saturated phosphatidylcholine (Phospholipon® 90H) as extended release excipient in matrix tablets for three model drugs with different aqueous solubility (theophylline, caffeine and diprophylline). The tablets could be prepared by direct compression because of the favorable phospholipid powder flow properties (Carr's index: 12.64 and angle of repose: 28.85) and good compactibility. Tablets of low porosity were formed already at low pressure of 40MPa and with drug loadings up to 70% due to high plasticity of the phospholipid. Extended drug release was achieved with the drugs of different solubility and at various drug loadings. For example, the caffeine release time (t80%) from 8mm tablets ranged from 1.5h to 18h at 70% and 10% drug loading, respectively. The drug release was governed by diffusion and could therefore be modelled by Fick's law of diffusion. Drug release profiles were thus a function of drug solubility, drug loading and tablet dimension. Matrix tablets of caffeine (20% drug loading) showed robust dissolution with regard to agitation (50-100rpm) and ionic strength of the release media (100-600 mOsmol/kg). Caffeine release was pH-dependent with a faster drug release at acidic pH, which was attributed to a protonization of the phosphatidyl group of the matrix-former and thus a higher hydrophilicity.

Localization of Chaotic Resonance States due to a Partial Transport Barrier.

Chaotic eigenstates of quantum systems are known to localize on either side of a classical partial transport barrier if the flux connecting the two sides is quantum mechanically not resolved due to Heisenberg's uncertainty. Surprisingly, in open systems with escape chaotic resonance states can localize even if the flux is quantum mechanically resolved. We explain this using the concept of conditionally invariant measures from classical dynamical systems by introducing a new quantum mechanically relevant class of such fractal measures. We numerically find quantum-to-classical correspondence for localization transitions depending on the openness of the system and on the decay rate of resonance states.

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 Fick's 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 Fick's 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.

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.

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.

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.

PLGA erosion: solubility- or diffusion-controlled?

PURPOSE: To 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. METHODS: The molecular weight distribution (MWD), degradation and erosion behaviour of PLGA were characterized by gel permeation chromatography. RESULTS: PLGA 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. CONCLUSION: The 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.

Improved lysozyme stability and release properties of poly(lactide-co-glycolide) implants prepared by hot-melt extrusion.

PURPOSE: To assess the feasibility of hot-melt extrusion (HME) for preparing implants based on protein/poly(lactide-co-glycolide) (PLGA) formulations with special emphasis on protein stability, burst release and release completeness. METHOD: Model protein (lysozyme)-loaded PLGA implants were prepared with a screw extruder and a self-built syringe-die device as a rapid screening tool for HME formulation optimization. Lysozyme stability was determined using DSC, FTIR, HPLC and biological activity. The simultaneous effect of lysozyme and PEG loadings was investigated to obtain optimized formulations with high drug loading but low initial release. RESULTS: Lysozyme was recovered from implants with full biological activity after HME. The release from all implants reached the 100% value in 60-80 days with nearly complete enzymatic activity of the last fraction of released lysozyme. Pure PLGA implants with up to 20% lysozyme loading could be formulated without initial burst. The incorporation of PEG 400 reduced the initial burst at drug loadings in excess of 20%. CONCLUSION: A complete lysozyme recovery in active form with a burst-free and complete release from PLGA implants prepared by hot-melt extrusion was obtained. This is in contrast to many reported microparticulate lysozyme-PLGA systems and suggests the great potential of hot-melt extrusion for the preparation of protein-PLGA implants.

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.