Multiple unit pellet systems and other types of multiparticulate oral solid dosage forms represent an attractive option to improve the effectiveness of delivering complex medicines targeted for modified release. Long-standing processing challenges relating to the coating and compression of multiparticulates has, until now, however constrained rates of market adoption. A new excipient manufacturing technology developed by Evonik has enabled the creation of a new, highly flexible combination polymer known as EUDRAGIT® FL 30 D-55. Requiring no additional plasticizer in the coating formulation, it is suitable for the compression of coated pellets to multiparticulate tablets. The new product can be sprayed with a smooth, non-sticking process for excellent adhesion and, as a single product, substantially reduce preparation times. Being able to form functional films at thin layers for efficient gastro-resistance, the polymer offers also advantages for highly dosed drugs.
Introduction
Scientific knowledge continues to improve regarding the gastrointestinal environment and inter-individual differences in drug action.1 This knowledge creates new opportunities to develop personalized medicines that can address gastrointestinal variations within patient populations, as well as other factors including age or associated diseases, to increase therapeutic effectiveness and reduce adverse side effects.2 Enabling technologies leading to advanced oral solid dosage forms with precisely defined modified release profiles are typically required to optimize the delivery of these specialized medicines.3
The use of multiparticulates for modified release formulations has significant advantages over conventional monolithic dosage forms.4 Due to the small size of each particle, the dosage form has a larger overall surface area from which it can deliver superior distribution along the gastrointestinal transit. In addition, high localized drug concentrations can be prevented to reduce the risk of local irritation, toxicity or other adverse side effects.5,6
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To act as an effective modified-release dosage form, multiparticulates are coated with a polymer and then either compressed into tablets or filled into hard gelatin capsules.7 Typically, the compaction of tablets is preferred over the use of hard-gelatin capsules, as they are easier, faster and more cost-effective to produce.8
One popular form of coated multiparticulates are multiple unit pellet systems, which are tablets composed of pellets that each contain the drug and a functional coating. Upon arrival in the gastrointestinal tract, the tablet disintegrates into its single pellets. Due to the different coating options of the individual pellets and their mixture, it is possible to process pellets with different release kinetics in one single formulation. Coated multiparticulates such as multiple unit pellet systems can also enable the combination of different drugs that are otherwise incompatible into a single dosage form.
Processing Challenges with Multiparticulates
It is integral that the polymeric coating surrounding each drug-loaded particle must retain its integrity, and withstand compaction forces during processing to remain its functionality. Damage to the coating (Figure 1) can significantly alter the release profile and dissolution behavior of the drug, resulting in the rapid release of the drug substance and the loss of intended modified release properties.9
The most important factor in preventing such adverse drug delivery outcomes is the type of coating layer that is utilized with multiparticulates. It is important that the polymeric coating can withstand the compression force by having the right combination of plasticity, elasticity, and thickness without rupturing. Flexible acrylic polymers such as EUDRAGIT® NM 30 D are generally preferred over cellulosic polymers for the coating of particulates for sustained release due to their relative elasticity, which makes them less likely to rupture under compression. The elasticity of these polymers is reflected in their elongation-at-break values (Figure 2).
Polymer films with elongation at break values greater than 100% can typically withstand the compressive forces experienced during the tableting process. Irregularly shaped or small particles can be difficult to coat, as they require a homogeneous coating around the edges to achieve target functionality. Processing has been too sticky up until now for standard flexible formulations, with it being difficult to obtain the right balance between elongation and stress break.10
Additional factors that can influence the successful development of multiparticulate formulations include the solubility of the drug in water, the combination of inter-granular porosity (air voids between pellets) and intra-granular porosity (air voids within pellets), pellet and tablet excipient composition and process parameters.11-13
Highly flexible coatings are required for the manufacturing process to withstand compression forces that would otherwise cause cracking.14 To achieve this goal, most gastroresistant products available in multiparticle unit dosage forms use either physical mixtures of enteric and highly flexible sustained release polymers, or large amounts of plasticizer. Both of these methods however have the disadvantage of being sticky during processing and storage, which can result in agglomeration of particles.
The use of high amounts of plasticizer can substantially increase the cost and complexity of processing, and introduce other storage-related challenges such as inhomogeneous distribution and evaporation. Meanwhile, the use of two separate polymers can also increase supply chain complexity, increase total preparation times, and require the use of several agitator vessels.
Advanced Excipient Manufacturing Process (AEMP™)
To address these and other challenges for advanced oral drug delivery, Evonik has developed a new proprietary Advanced Excipient Manufacturing Process (AEMP™) technology. This novel technology is able to alter excipient functionality by combining the favorable characteristics of multiple polymers. The technology is designed to physically modify polymer properties in a manner that is not achievable by simple physical mixing and without significant chemical change. Furthermore, because new products developed with the new technology are based on existing, well-established polymers with a strong safety record, regulatory risks and development costs are not higher than using single polymers.
EUDRAGIT® FL 30 D-55
Evonik has leveraged its AEMP™ technology to combine the respective benefits of two existing, monographed polymers from its EUDRAGIT® portfolio to create a new product marketed as EUDRAGIT® FL 30 D-55. This new combination product, which is not classified as a novel excipient, contains EUDRAGIT® L 30 D-55 and EUDRAGIT® NM 30 D. Due to its dominating gastro-resistant functionality, EUDRAGIT® L 30 D-55 serves as the lead polymer, while EUDRAGIT® NM 30 D provides higher levels of flexibility.
Being highly flexible, EUDRAGIT® FL 30 D-55 can be sprayed with a smooth, fast and nostick process and does not require additional plasticizer in the coating formulation to form homogeneous films at low process temperatures.
EUDRAGIT® FL 30 D-55 has an elongation at break value of 200%, which demonstrates its high flexibility. Accordingly, there is no need to use plasticizers in the coating formulation to increase fi lm flexibility. Plasticizer addition is not either required to decrease the minimum fi lm forming temperature (MFT) of EUDRAGIT® FL 30 D-55, which already has a low MFT value of <10°C. As a result of the new AEMP™ technology, the new product is less sticky when compared to the physical mixtures which enables a fast and no-stick process.
Based upon the combination of the two different polymers that comprise EUDRAGIT® L30D-55, the new product exhibits both pH and time dependent release characteristics. This enables the design of gastro resistant release profiles that incorporate rapid drug release after transit through the stomach. However, by applying higher polymer amounts, it is also possible to combine rapid drug release after stomach transit with a sustained release functionality depending on the polymer amount applied.
The Use of Multiple Unit Pellet Systems with EUDRAGIT FL® 30 D-55
The flexibility of EUDRAGIT® FL 30 D-55 and its suitability for use with multi particle unit systems was demonstrated in a case study with the model drug theophylline. Regularly shaped theophylline pellets were coated with 12% EUDRAGIT® FL 30 D-55 and compressed into round multiple unit pellet system tablets of 11 mm diameter with a hardness of 120 to 140 N. Also studied were irregularly shaped theophylline granules coated with 10% EUDRAGIT® FL 30 D-55 that were compressed into round multiple unit particle system tablets of 11 mm diameter with a hardness of 120 to 140 N (Table 1). The respective dissolution profiles showed that gastro-resistance for EUDRAGIT® FL 30 D-55 can be maintained during compression of the coated pellets and granules, that there is no change in the dissolution profile after compression, and that release occurs rapidly after stomach transit (Figure 3). SEM pictures of the particles after compression show that the films of the pellets as well as of the granules have not formed any cracks during compression (Figure 4).
To compare the technical beneficial properties of EUDRAGIT® FL 30 D-55 with the standard physical mixture, theophylline pellets were also coated with a physical mixture of EUDRAGIT® L 30 D-55 and EUDRAGIT® NM 30 D.
To measure the sticking behavior of coated pellets the deformation and sticking after application of force in a confined tube was measured with a texture analyzer to compare the properties of pellets reflective of its storage behavior. Effective retained deformation was lower for EUDRAGIT®
FL 30 D-55 coated pellets compared to pellets coated with the physical mixture of the single polymers indicating lower cohesive forces (Figure 5).
In order to investigate possible curing effects, theophylline pellets coated with EUDRAGIT FL® 30 D-55 were dried at 40°C in an air oven for 2 hours compared to 24 hours. The release profiles did not show any alterations, indicating that coated pellets do not require any curing.
Additional Opportunities
EUDRAGIT® FL 30 D-55 has a very low acid value, which can make it highly compatible with a broad range of APIs such as acid-sensitive small molecules or peptides. Smaller particles have higher surface areas, and thus require more polymer to achieve the required film thickness to obtain the desired functionality. If target functionalities can be already obtained with low polymer levels, the volume of excipient per dosage form can be reduced, creating opportunities for high drug loadings.
Summary
EUDRAGIT® FL 30 D-55 represents a new class of highly flexible enteric coating for use with small molecules, peptides, proteins, enzymes and other complex drugs targeted for use with coated multiparticulates and tablets made thereof. It can be sprayed with a smooth, fast and no-stick process for excellent adhesion. As a single product, spray suspension preparation times can be reduced by up to 70%, while lowering manufacturing costs and total required polymer volumes. It has also been shown to create robust functionality at low coating thickness, creating opportunities for high drug loading in multiparticulate formulations with a small particle size.
Author Biographies
Dr. Müller-Albers is the Strategic Marketing Director for Oral Drug Delivery Solutions at Evonik. Prior to her current role, she was responsible for the development of formulation technologies for the oral and parenteral delivery of pharmaceutical and nutraceutical products. She has a PhD in Pharmaceutical Technology from the University of Dusseldorf in Germany.
Ashish Guha is the Associate Director of Formulations for Evonik in India, where he specializes in the development of formulation technologies for the oral delivery of pharmaceutical and nutraceutical products. He has more than 15 years of experience in pharmaceutical formulation development, technology transfer, manufacturing and drug delivery.
Manfred Assmus is the Head of Product Development Oral Excipients for Pharmaceutical Polymers at Evonik, where he manages the development of innovative new products for oral drug delivery. He has more than 30 years of polymer development, formulation, application and process technology expertise with oral solid dosage forms for the pharmaceutical and nutraceutical markets.
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