Factors That Influence Sustained Release from Hot-Melt Extrudates

Hot-melt extrusion is a well-established tool in the pharmaceutical industry, mostly implemented to increase the solubility of poorly soluble drugs. A less frequent application of this technique is to obtain formulations with extended release. This study investigated the influence of polymer choice, drug loading, milling and hydrodynamics on the release of a model drug, flurbiprofen, from sustained-release hot-melt extrudates with Eudragit polymers. The choice of polymer and degree of particle size reduction of the extrudate by milling were the two key influences on the release profile: the percentage release after 12 h varied from 6% (2 mm threads) to 84% (particle size <125 µm) for Eudragit RL extrudates vs. 4.5 to 62% for the corresponding Eudragit RS extrudates. By contrast, the release profile was largely independent of drug loading and robust to hydrodynamics in the dissolution vessel. Thus, hot-melt extrusion offers the ability to tailor the release of the API to the therapeutic indication through a combination of particle size and polymer choice while providing robustness over a wide range of hydrodynamic conditions.

1. Introduction

Hot-melt extrusion is a well-established tool in the pharmaceutical industry, mostly implemented to increase the solubility of poorly soluble drugs [1,2,3]. In this process, a mixture of the active pharmaceutical ingredient (API), a polymer (often based on acrylates, lactic acid, or cellulose derivatives) and a plasticizer, e.g., stearic or triethyl citric acid, is continuously fed into a single or twin-screw extruder and melted at a specific temperature. Simultaneously, the mixture is kneaded by the screws and thereby homogenized. Drug-loaded filaments are produced by propagating the mixture through a die with a defined diameter [1,2].

These filaments can be processed further to produce various shapes and sizes. For example, the filaments can be cut into equal-sized pieces while still soft and then spheronized to produce pellets. They can be milled to produce powders of defined particle size [2,3,4,5,6,7,8] or, in the most recent applications, used in the 3D printing of solid drug formulations via fused deposition modeling [9,10,11,12]. Depending on the choice of polymer, hot-melt extrudates can be used to improve the bioavailability of poorly soluble drugs, as biodegradable/non-biodegradable drug-loaded implants or, less often, as oral sustained-release dosage forms [2,3,4,5,6,7,8].

The aim of the current project was to understand how various formulation parameters influence the dissolution performance of sustained-release hot-melt extrudates using flurbiprofen as a model drug. Flurbiprofen, an NSAID (non-steroidal anti-inflammatory drug), is well established for use as a spray or lozenge to alleviate sore throat (e.g., Dobendan Direkt©) and in oral dosage forms (e.g., Froben© tablets, capsules) for the therapy of rheumatic diseases [13,14,15,16]. In the latter case, sustained release of flurbiprofen would be advantageous in attaining a constant therapeutic effect and reducing the frequency of administration since this API has a short half-life of around 5 h [17].

Poorly soluble Eudragit polymers and those with pH-dependent solubility are often used in oral pharmaceutical products as a coating material to modify drug release from a dosage form. Those with pH-dependent solubility are also widely used in hot-melt extrusion (HME) and 3D printing [1,2,3,4,5,9,10,11,12]. In this research, Eudragit RL and RS were used to obtain sustained-release solid oral dosage forms by HME processing. These two Eudragit polymers are both non-erodible, cationic polymers belonging to the polymethacrylate family. Both are insoluble in water and release the active pharmaceutical ingredient (API) via diffusion in a pH-independent manner [2,18]. Both polymers, either alone or in mixtures at different ratios, have been widely implemented for the formulation of sustained-release dosage forms, mostly in film coatings [2,18,19,20,21,22,23,24,25,26,27,28,29]. While their molecular structure is nearly the same, the number of ammonium groups and, therefore, the permeability of these two polymers differ [2,18].

In these studies, flurbiprofen/Eudragit extrudates were investigated to assess (a) the ability of the extrudates to retard API release, (b) the effect of particle size on the dissolution performance and (c) development aspects such as extrudability, maximum achievable drug load, homogeneity, and extent of (re)-crystallization. To date, no publications have appeared in the literature addressing all these points systematically for hot-melt extrudates with Eudragit RL and RS. The dissolution of an API from a hot-melt extrudate using Eudragit RL or RS should depend mainly on its diffusion through the polymer to the surface of the extrudate. As the surface area, and consequently, the particle size, affects the diffusion rate of a molecule, the relationship between the particle size of the extrudate and the release pattern of the API from the extrudate is of particular interest.

2.1. Materials

Flurbiprofen, 98% pure (as the racemate), was purchased from Alfa Aesar (Thermo Fisher GmbH, Kandel, Germany). Eudragit RL PO and RS PO were kindly donated by Evonik Industries AG. Talcum, magnesium stearate and stearic acid were obtained from VWR chemicals (Darmstadt, Germany). The commercial product Cebutid^® LP 200 mg (Batch number: 2002) was obtained from Almirall SAS (Paris, France). FaSSIF V1 powder was purchased from Biorelevant.com Ltd. (London, United Kingdom), and FaSSIF V1 was prepared using the standard operating procedures provided by Biorelevant.com Ltd. (Biorelevant.com). Acetonitrile and TFA (Trifluoroacetic acid) used for HPLC analysis were obtained commercially from VWR chemicals (Darmstadt, Germany) and Merck KGaA (Darmstadt, Germany), respectively.

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Mansuroglu, Y.; Dressman, J. Factors That Influence Sustained Release from Hot-Melt Extrudates. Pharmaceutics 2023, 15, 1996.
https://doi.org/10.3390/pharmaceutics15071996

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