Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation-Where Are We Now?

Hot-melt extrusion (HME) is a globally recognized, robust, effective technology that enhances the bioavailability of poorly soluble active pharmaceutical ingredients and offers an efficient continuous manufacturing process. The twin-screw extruder (TSE) offers an extremely resourceful customizable mixer that is used for continuous compounding and granulation by using different combinations of conveying elements, kneading elements (forward and reverse configuration), and distributive mixing elements. TSE is thus efficiently utilized for dry, wet, or melt granulation not only to manufacture dosage forms such as tablets, capsules, or granule-filled sachets, but also for designing novel formulations such as dry powder inhalers, drying units for granules, nanoextrusion, 3D printing, complexation, and amorphous solid dispersions. Over the past decades, combined academic and pharmaceutical industry collaborations have driven novel innovations for HME technology, which has resulted in a substantial increase in published articles and patents. This article summarizes the challenges and models for executing HME scale-up. Additionally, it covers the benefits of continuous manufacturing, process analytical technology (PAT) considerations, and regulatory requirements. In summary, this well-designed review builds upon our earlier publication, probing deeper into the potential of twin-screw extruders (TSE) for various new applications.

3D printing in vaginal drug delivery: a revolution in pharmaceutical manufacturing.

INTRODUCTION: The Food and Drug Administration's approval of the first three-dimensional (3D) printed tablet, Spritam®, led to a burgeoning interest in using 3D printing to fabricate numerous drug delivery systems for different routes of administration. The high degree of manufacturing flexibility achieved through 3D printing facilitates the preparation of dosage forms with many actives with complex and tailored release profiles that can address individual patient needs. AREAS COVERED: This comprehensive review provides an in-depth look into the several 3D printing technologies currently utilized in pharmaceutical research. Additionally, the review delves into vaginal anatomy and physiology, 3D-printed drug delivery systems for vaginal applications, the latest research studies, and the challenges of 3D printing technology and future possibilities. EXPERT OPINION: 3D printing technology can produce drug-delivery devices or implants optimized for vaginal applications, including vaginal rings, intra-vaginal inserts, or biodegradable microdevices loaded with drugs, all custom-tailored to deliver specific medications with controlled release profiles. However, though the potential of 3D printing in vaginal drug delivery is promising, there are still challenges and regulatory hurdles to overcome before these technologies can be widely adopted and approved for clinical use. Extensive research and testing are necessary to ensure safety, effectiveness, and biocompatibility.

Continuous Manufacturing of Solvent-Free Cyclodextrin Inclusion Complexes for Enhanced Drug Solubility via Hot-Melt Extrusion: A Quality by Design Approach.

Conventional cyclodextrin complexation enhances the solubility of poorly soluble drugs but is solvent-intensive and environmentally unfavorable. This study evaluated solvent-free hot-melt extrusion (HME) for forming cyclodextrin inclusion complexes to improve the solubility and dissolution of ibuprofen (IBU). Molecular docking confirmed IBU's hosting in Hydroxypropyl-ß-cyclodextrin (HPß-CD), while phase solubility revealed its complex stoichiometry and stability. In addition, an 11 mm twin-screw co-rotating extruder with PVP VA-64 as an auxiliary substance aided the complex formation and extrusion. Using QbD and the Box-Behnken design, we studied variables (barrel temperature, screw speed, and polymer concentration) and their impact on solubility and dissolution. The high polymer concentration and high screw speeds positively affected the dependent variables. However, higher temperatures had a negative effect. The lowest barrel temperature set near the Tg of the polymer, when combined with high polymer concentrations, resulted in high torques in HME and halted the extrusion process. Therefore, the temperature and polymer concentration should be selected to provide sufficient melt viscosities to aid the complex formation and extrusion process. Studies such as DSC and XRD revealed the amorphous conversion of IBU, while the inclusion complex formation was demonstrated by ATR and NMR studies. The dissolution of ternary inclusion complexes (TIC) produced from HME was found to be ≥85% released within 30 min. This finding implied the high solubility of IBU, according to the US FDA 2018 guidance for highly soluble compounds containing immediate-release solid oral dosage forms. Overall, the studies revealed the effect of various process parameters on the formation of CD inclusion complexes via HME.

Drug complexes: Perspective from Academic Research and Pharmaceutical Market.

Despite numerous research efforts, drug delivery through the oral route remains a major challenge to formulation scientists. The oral delivery of drugs poses a significant challenge because more than 40% of new chemical entities are practically insoluble in water. Low aqueous solubility is the main problem encountered during the formulation development of new actives and for generic development. A complexation approach has been widely investigated to address this issue, which subsequently improves the bioavailability of these drugs. This review discusses the various types of complexes such as metal complex (drug-metal ion), organic molecules (drug-caffeine or drug-hydrophilic polymer), inclusion complex (drug-cyclodextrin), and pharmacosomes (drug-phospholipids) that improves the aqueous solubility, dissolution, and permeability of the drug along with the numerous case studies reported in the literature. Besides improving solubility, drug-complexation provides versatile functions like improving stability, reducing the toxicity of drugs, increasing or decreasing the dissolution rate, and enhancing bioavailability and biodistribution. Apart, various methods to predict the stoichiometric ratio of reactants and the stability of the developed complex are discussed.

Nanoemulgel: A Novel Nano Carrier as a Tool for Topical Drug Delivery.

Nano-emulgel is an emerging drug delivery system intended to enhance the therapeutic profile of lipophilic drugs. Lipophilic formulations have a variety of limitations, which includes poor solubility, unpredictable absorption, and low oral bioavailability. Nano-emulgel, an amalgamated preparation of different systems aims to deal with these limitations. The novel system prepared by the incorporation of nano-emulsion into gel improves stability and enables drug delivery for both immediate and controlled release. The focus on nano-emulgel has also increased due to its ability to achieve targeted delivery, ease of application, absence of gastrointestinal degradation or the first pass metabolism, and safety profile. This review focuses on the formulation components of nano-emulgel for topical drug delivery, pharmacokinetics and safety profiles.

Additive manufacturing technologies with emphasis on stereolithography 3D printing in pharmaceutical and medical applications: A review.

Three-dimensional (3D) printing or Additive Manufacturing (AM) technology is an innovative tool with great potential and diverse applications in various fields. As 3D printing has been burgeoning in recent times, a tremendous transformation can be envisaged in medical care, especially the manufacturing procedures leading to personalized medicine. Stereolithography (SLA), a vat-photopolymerization technique, that uses a laser beam, is known for its ability to fabricate complex 3D structures ranging from micron-size needles to life-size organs, because of its high resolution, precision, accuracy, and speed. This review presents a glimpse of varied 3D printing techniques, mainly expounding SLA in terms of the materials used, the orientation of printing, and the working mechanisms. The previous works that focused on developing pharmaceutical dosage forms, drug-eluting devices, and tissue scaffolds are presented in this paper, followed by the challenges associated with SLA from an industrial and regulatory perspective. Due to its excellent advantages, this technology could transform the conventional "one dose fits all" concept to bring digitalized patient-centric medication into reality.

Formulating Ternary Inclusion Complex of Sorafenib Tosylate Using ß-Cyclodextrin and Hydrophilic Polymers: Physicochemical Characterization and In Vitro Assessment.

Sorafenib tosylate (SFNT) is the first-line drug for hepatocellular carcinoma. It exhibits poor solubility leading to low oral bioavailability subsequently requiring intake of large quantities of drug to exhibit desired efficacy. The present investigation was aimed at enhancing the solubility and dissolution rate of SFNT using complexation method. The binary inclusion complex was prepared with ß-cyclodextrin (ß-CD). The molecular docking studies confirmed the hosting of SFNT into hydrophobic cavity of ß-CD, while the phase solubility studies revealed the stoichiometry of complexation with a stability constant of 735.8 M-1. The ternary complex was prepared by combining the SFNT-ß-CD complex with PEG-6000 and HPMC polymers. The results from ATR-IR studies revealed no interaction between drug and excipients. The decreased intensities in ATR-IR peaks and changes in chemical shifts from NMR of SFNT in complexes indicate the possibility of SFNT hosting into the hydrophobic cavity of ß-CD. The disappearance of SFNT peak in DSC and XRD studies revealed the amorphization upon complexation. The ternary complexes exhibited improved in vitro solubility (17.54 µg/mL) compared to pure SFNT (0.19 µg/mL) and binary inclusion complex (1.52 µg/mL). The dissolution profile of ternary inclusion complex in 0.1 N HCl was significantly higher compared to binary inclusion complex and pure drug. In cytotoxicity studies, the ternary inclusion complex has shown remarkable effect than the binary inclusion complex and pure drug on HepG2 cell lines.

Effect of Chrysin on Mechanical Hyperalgesia in Chronic Constriction Injury-Induced Neuropathic Pain in Rat Model.

OBJECTIVE: The present study aimed to assess the effect of Chrysin on mechanical hyperalgesia in chronic constriction injury (CCI)-induced neuropathic pain in Wistar rats. MATERIALS AND METHODS: Neuropathic pain was induced by CCI to the sciatic nerve in rats. Oral treatment of chrysin was given at doses of 50 mg/kg, 100 mg/kg, and 200 mg/kg in neuropathic rats. Mechanical hyperalgesia (in terms of paw withdrawal threshold [PWT]) was measured using Randall-Selitto analgesy-meter, and percent PWT was determined. Statistical analysis was carried out using GraphPad Prism 5 tool. RESULTS: In mechanical hyperalgesia test, treatment with chrysin 200 mg/kg, naive PWT, predose PWT, 0.5 h, 1 h, 2 h, and 4 h postdose PWT were found to be 141 ± 8.94 g, 60 ± 7.91 g, 107 ± 9.08 g, 113 ± 5.70 g, 106.0 ± 7.42 g, and 97 ± 9.08 g, respectively. The peak effect was observed at 2 h posttreatment for 50 mg and 100 mg while the peak effect for 200 mg was reached at 1 h, and the same was maintained till 2 h posttreatment. Chrysin 200 mg dose has shown maximal percent reversal (74%) at 2 h posttreatment. The percent reversal PWT of 50 mg/kg, 100 mg/kg, and 200 mg/kg at 2 h were 68%, 67%, and 74%, respectively. Chrysin has exhibited dose-dependent efficacy in CCI-induced neuropathic pain. In mechanical allodynia test, In chrysin (200 mg/kg) treatment group, naive PWT, predose PWT, 0.5 h, 1 h, 2 h, and 4 h postdose PWT were found to be 60.0 ± 0.0 g, 5.0 ± 1.10 g, 22.45 ± 6.62 g, 52.64 ± 18.29 g, 37.33 ± 17.56 g, and 29.83 ± 9.22 g, respectively. The percent reversal PWT of 50 mg/kg, 100 mg/kg, and 200 mg/kg at 2 h were 43%, 68%, and 87%, respectively. CONCLUSION: Chrysin attenuates neuropathic pain by ameliorating mechanical hyperalgesia and allodynia. Further studies are warranted to establish the mechanism.