F. Siepmann

Mathematical modeling of drug release from lipid dosage forms

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

Drug release mechanisms from Kollicoat SR:Eudragit NE coated pellets.

Thin, free films based on Kollicoat SR:Eudragit NE blends were prepared by casting or spraying aqueous dispersions of these polymers, and were thoroughly characterized with respect to their water uptake behavior, water permeability, dry mass loss kinetics, mechanical properties and drug release patterns. A mechanistic mathematical model based on Ficks law of diffusion was used to quantify the experimentally measured release of metoprolol succinate from various types of systems. With increasing Eudragit NE content the films became more hydrophobic, resulting in decreased water permeability as well as water uptake rates and extents. In addition, the dry mass loss upon exposure to the release medium decreased. Consequently, the films permeability for the drug decreased. Importantly, metoprolol succinate release from thin films was mainly controlled by pure diffusion, allowing for the determination of the apparent diffusion coefficient of the drug in the different polymeric systems. Knowing these values, drug release from coated pellets could be quantitatively predicted, assuming intact film coatings throughout the observation period. Comparison with independent experimental results showed that crack formation set on very rapidly in the polymeric membranes upon exposure to the release medium in the case of sugar starter cores, irrespective of the polymer:polymer blend ratio and investigated coating level. In contrast, the onset of crack formation was delayed as a function of the blend ratio and coating thickness in the case of microcrystalline cellulose starter cores, attracting less water into the pellets core. The obtained new insight into the underlying drug release mechanisms can be very helpful during device optimization and improve the safety of this type of advanced drug delivery systems.

Drug release mechanisms of compressed lipid implants.

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

Does PLGA microparticle swelling control drug release? New insight based on single particle swelling studies

The aim of this study was to better understand the mass transport mechanisms controlling drug release from PLGA microparticles. New insight was gained based on the experimental monitoring of single microparticle swelling. An oil-in-water (O/W) solvent extraction/evaporation method was used to prepare ketoprofen-loaded microparticles, varying the initial drug loading from 0.6 to 45.2%. Importantly, the microparticle size was kept about constant. At low ketoprofen loadings, the release patterns were clearly tri-phasic: an initial burst release was followed by a period with an about constant release rate and a final (again rapid) drug release phase. With increasing initial drug content the onset of the third release period was shifted to earlier time points. At even higher drug loadings, the release patterns became more or less bi- or mono-phasic. Interestingly, all types of microparticles showed substantial swelling after a lag-time, which coincided with the onset of the third (and again rapid) drug release phase at low loadings and proceeded it by 1 or 2d at higher drug loadings. The substantial microparticle swelling set on as soon as a critical PLGA molecular weight was reached (around 20 kDa). Thus, the onset of the third drug release phase from the PLGA microparticles might be explained as follows: once the macromolecules are sufficiently short, substantial amounts of water penetrate into the system, significantly increasing the mobility of the drug within the microparticles and resulting in increased drug release rates.

In situ forming implants for periodontitis treatment with improved adhesive properties

Novel in situ forming implants are presented showing a promising potential to overcome one of the major practical hurdles associated with local periodontitis treatment: limited adhesion to the surrounding tissue, resulting in accidental expulsion of at least parts of the implants from the patients pockets. This leads to high uncertainties in the systems residence times at the site of action and in the resulting drug exposure. In the present study, the addition of different types and amounts of plasticizers (acetyltributyl citrate and dibutyl sebacate) as well as of adhesive polymers (e.g., cellulose derivatives such as hydroxypropyl methylcellulose) is shown to allow for a significant increase in the stickiness of poly(lactic-co-glycolic acid)-based implants. The systems are formed in situ from N-methyl pyrrolidone-based liquid formulations. Importantly, at the same time, good plastic deformability of the implants can be provided and desired drug release patterns can be fine-tuned using several formulation tools. The antimicrobial activity of this new type of in situ forming implants, loaded with doxycycline hyclate, was demonstrated using the agar well diffusion method and multiple Streptococcus strains isolated from the oral microflora of patients suffering from periodontitis.

Ethanol-resistant polymeric film coatings for controlled drug delivery

The sensitivity of controlled release dosage forms to the presence of ethanol in the gastro intestinal tract is critical, if the incorporated drug is potent and exhibits severe side effects. This is for instance the case for most opioid drugs. The co-ingestion of alcoholic beverages can lead to dose dumping and potentially fatal consequences. For these reasons the marketing of hydromorphone HCl extended release capsules (Palladone) was suspended. The aim of this study was to develop a novel type of controlled release film coatings, which are ethanol-resistant: even the presence of high ethanol concentrations in the surrounding bulk fluid (e.g., up to 40%) should not affect the resulting drug release kinetics. Interestingly, blends of ethylcellulose and medium or high viscosity guar gums provide such ethanol resistance. Theophylline release from pellets coated with the aqueous ethylcellulose dispersion Aquacoat® ECD 30 containing 10 or 15% medium and high viscosity guar gum was virtually unaffected by the addition of 40% ethanol to the release medium. Furthermore, drug release was shown to be long term stable from this type of dosage forms under ambient and stress conditions (without packaging material), upon appropriate curing.

Stability of aqueous polymeric controlled release film coatings.

Aqueous polymeric film coatings provide a great potential to accurately control the release rate of a drug from a pharmaceutical dosage form, while avoiding the various disadvantages associated with the use of organic solvents. However, long term instability of drug release, due to imperfect film formation during coating and curing, can be a serious concern. If the coalescence of the particles continues during storage, the film permeability can decrease, slowing down drug release. Different strategies can be used to effectively avoid this phenomenon, including optimized curing conditions, the addition of appropriate additives and the use of specific packaging materials. This article gives an overview on the current state of the art in this field. Various practical examples are described, covering different types of polymer coatings and drugs. The aims are: (i) to provide a better understanding of the release patterns and potential changes thereof, and (ii) to help identifying strategies allowing for improved long term stability for specific types of polymer coatings.

Drug release mechanisms of cast lipid implants

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

PLGA microparticles with zero-order release of the labile anti-Parkinson drug apomorphine

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

Dynamic and static curing of ethylcellulose:PVA–PEG graft copolymer film coatings

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