Chronotherapeutic Drug Delivery of Ketoprofen and Ibuprofen for Improved Treatment of Early Morning Stiffness in Arthritis Using Hot-Melt Extrusion Technology

Abstract

This work developed a chronotherapeutic drug delivery system (CTDDS) utilizing a potential continuous hot-melt extrusion (HME) technique. Ketoprofen (KTP) and ibuprofen (IBU) were used as two separate model drugs. Eudragit S100 (ES100) was the matrix-forming agent, and ethyl cellulose (EC) (2.5 and 5%) was the release-retarding agent. A 16-mm extruder was used to develop the CTDDS to pilot scale. The obtained extrudate strands were transparent, indicating that the drugs were homogeneously dispersed in the matrix in an amorphous form, confirmed by both differential scanning calorimetry and powder X-ray diffraction. The strands were pelletized into 1, 2, and 3 mm size pellets. A 100% drug release from 1, 2, and 3 mm pellets with 2.5% EC was observed at 12, 14, and 16 h, whereas the drug release was sustained for 14, 16, and 22 h from 5% EC pellets, respectively, for KTP. The release characteristics of IBU were similar to those of KTP with modest variations in release at lag time. The in vitro drug release study conducted in three-stage dissolution media showed a desired lag time of 6 h. The percent drug release from 1, 2, and 3 mm pellets with 40% drug load showed < 20% release from all formulations at 6 h. The amount of ethyl cellulose and pellet size significantly affected drug release. Formulations of both KTP and IBU were stable for 4 months at accelerated stability conditions of 40°C/75% RH. In summary, HME is a novel technique for developing CTDDS.

Novel Gastroretentive Floating Pulsatile Drug Delivery System Produced via Hot-Melt Extrusion and Fused Deposition Modeling 3D Printing

“…Over the last three decades, its use in drug delivery and research has tremendously increased owing to the advantages associated with this technology, such as high efficiency, solvent-free, innovative applications, and continuous manufacturing [17]. Although HME is most widely used in the preparation of amorphous solid dispersions, it is also used in the development of many innovative applications, such as taste masking, abuse-deterrent formulations, chronotherapeutic systems, topical formulations, semi-solid dosage forms, and co-amorphous systems [18][19][20][21][22]. Recently, the interest of researchers has shifted to additive manufacturing of pharmaceutical dosage forms where HME is combined with three-dimensional (3D) printing.…”

Influence of screw configuration and processing parameters on the dissolution of ketoprofen in polymer blends

“…Similar results were found in the literature, where it was not possible to process samples with concentrations higher than 30% of KTO due to their elastic appearance after the cooling process. [21,38,39] Due to the elastic behavior of the samples at room temperature, it was necessary to store the samples in a space with controlled temperature, below 10 C. It was observed that the samples not stored in a space with controlled temperature, their milling was difficult, the powder showed tendency to agglomerate and the hard capsules were left with air inside, which caused them to float affecting negatively the KTO release profile. All samples analyzed were stored in a refrigerator.…”

“…There is information in the literature about processing binary samples (API and one polymer excipient) by HME. [11,12,14,[17][18][19]21,40] The present investigation was done with ternary samples, an API and two polymeric excipients. Although, there is not much information about the interaction of polymeric excipients with each other or with the API.…”

“…The authors reported a sustained release profile using different pH in different dissolution media. [21] Although some of the previous works studied the dissolution of an API in a polymeric excipient under different HME processing conditions, little information was found on the specific processing parameters such as temperature profile, fill factor, screw rotation speed, different screw configurations, among others. In addition, the information included mainly analysis of binary formulations, an API and a polymeric excipient.…”

An update on the contribution of hot-melt extrusion technology to novel drug delivery in the twenty-first century: part I

“…Lately, HME is being explored for various applications, and it is found successful in the development of various drug delivery strategies. Literature reports showed the use of HME in the development of pharmaceutical cocrystals [8], co-extrusion for producing fixed-dose combinations [9], chronotherapeutic systems [10], self-emulsifying drug delivery systems [11], twin-screw granulation [12], semisolid dosage forms [13], abuse-deterrent formulations [14], novel three-dimensional (3D) printing filaments [15], and other miscellaneous applications [2,3,4,16]. Figure 1 illustrates the volume of research publications on HME for preparing different drug delivery sytems during the last five years.…”