Hot Melt Extrusion (HME), also known as Melt Extrusion technique, refers to a technology in which drugs and carrier excipients are uniformly mixed in a molten state and extruded with a certain pressure, speed and shape. The technology enables the drug to be dispersed in the carrier in molecular, amorphous or metastable forms, which can improve the solubility and bioavailability of insoluble drugs. It is a new formulation technology developed rapidly in recent years, showing advantages in preparing sustained and controlled release formulations and in drug delivery system with low cost, simple process, better reproducibility and high production efficiency, so that it has broad development prospects in the field of pharmaceutical R&D.
1. Principle and characteristics of HME
In preparing HME, the drug is first premixed with a thermoplastic polymeric carrier and other excipients and then filled in a single or double screw extruder, where the rotating screw drives the physical mixture for further extrusion while the extruder interlayer heats it at high temperature. The drug and the excipients are favorably compatible under the strong heat power and shearing force with transforming from a multi-phase state at the inlet to a single-phase state at the outlet and extruding through the outlet die hole. The extruded intermediates can be prepared into various solid formulations by post-processing, including tablets, capsules, membranes, pellet or powder form of prescriptions, granules and others which can be widely applied in producing preparations such as improving the bioavailability of insoluble drugs, taste masking and obtaining controlled drug release.
Compared with traditional formulation technology, the HME has the advantages of integrating various unit operations (solid delivery, material melting, shear mixing, melt mass delivery, extrusion and others), facilitating industrial production and solvent-free residue, etc. It is especially suitable for wet-sensitive drugs, by selecting different carriers to increase drug solubility and bioavailability, sustained and controlled release, enteric dissolution or taste masking effects, and can be made into many preparations such as capsules, tablets, micro-pills, implants for oral, transdermal, mucosal and implantable drug delivery in line with different requirements.
2. Application of HME in drug delivery system
2.1 Improve the solubility and bioavailability of drugs
Solid dispersion technology has prominent results in improving drug solubility and is considered to be one of the most promising technologies. HME is widely applied in the preparation of solid dispersions. With HME, drugs and carrier materials are mixed in a certain ratio, then become molten under slow heat and solidified by rapid stirring under quenching to obtain solid dispersions. It is a simple and economical method that can highly increase the drug solubility and improve the dissolution effect of insoluble drugs, improving the bioavailability; Solvents may be not utilized in the preparation. Possible solvent-related stability risks in formulation storage are avoided as no residual solvents are left.
2.2 Sustained and controlled release formulations
Sustained/controlled release drug delivery system is always a topical issue in drug R&D, which is characterized by low toxic and side effects and smooth plasma-drug concentration. Many methods are available for the preparation of sustained release formulations, and since hot melt extrudates are featured with high density and low porosity, it is possible to prepare the sustained/controlled release drug delivery system with a high drug loading capacity. The thermoplastic carrier material for sustained and controlled release is extruded with water-soluble drug by hot melt to reduce the dissolution rate, and the resulting extrudate can be sheared or pressed into suitable formulations. Polyoxyethylene matrix sustained release tablets of chlorpheniramine were prepared by direct powder compression and hot melt extrusion respectively with polyethylene oxide as drug carrier and PEG 3350 as plasticizer. Compared with the direct compression process of powder, the strong shearing mixing of the screw in the hot melt extrusion reduces the porosity, decreases the pore size and increases the curvature of the polyoxyethylene skeleton with significantly better sustained release effect than the ordinary compressed tablets.
2.3 Preparation of targeting formulations
Targeting formulations can deliver drugs to target tissues, target organs or target cells in a targeted manner, which can improve drug efficacy while reducing or even avoiding side effects, with significant advantages compared to traditional formulations. HME has been applied in targeting formulation researches with flexible choice of carrier materials and excipients. The colon-targeting formulation containing photosensitizer prepared with Eudragit S100 as a carrier is capable of targeted release at the colonic site and has a better therapeutic effect on diseases caused by drug fast bacteria. A floating agent of nicardipine hydrochloride was prepared by a double screw extruder. The formulation contains many pores to float in the gastric juice permanently for exerting its medicinal effect.
2.4 Masking the peculiar smell of drugs
Some drugs are bitter on their own or tend to give a strong bitter flavor to the taste buds when dissolved by saliva. In the research of orally disintegrating tablets, it is a major challenge to mask the off-flavor of the active ingredients of the drug. The active ingredients of drug and high-molecular polymer form intermolecular interactions by the HME so that the bitter drug is encapsulated in the carrier material to prevent direct contact between the bitter-tasting drug and the patient's taste buds with achieving a significant taste masking effect. It was found by research that Eudragit EPO or Kollidon VA64 had superior taste masking effect on paracetamol with the best taste masking effect by using VA64 as a substrate at 30% drug loading capacity. The bitter taste of ibuprofen was vastly improved by preparing ibuprofen into orally disintegrating tablets with Eudragit EPO as the carrier employing HME.
Moreover, the HME can also be applied to the research of formulations such as membrane, suppository and implant. Currently, products such as Nuvaring, a vaginal contraceptive ring, and Implanon, a contraceptive implant, are available on the market.
As a new formulation technology, HME is featured with better dispersion, absence of organic solvents as well as continuous and controllable process. The application of the technology in various formulations of sustained and controlled release formulations has developed considerably and has become the leading technology for preparing solid dispersions at home and abroad in recent years. The selection of a suitable carrier is crucial in the hot melt extrusion. The compatibility of drug and carrier affects the product performance significantly, and the pores of the carrier material with its microporous structure have a significant effect on the release rate of the drug. HME will be developed further in the pharmaceutical field with the continuous development, improvement and application research of formulation process and new carriers.
References:
[1] Meng Jia. Application of Hot Melt Extrusion Technology in Pharmaceutical Preparations [J]. Electronic Journal of Clinical Medical Literature, 2019, 612: 192-193.
[2] Liu Danping, Zeng Jia, Tian Mingbo, Pu Tianlei, Pan Feng, Feng Linglin, Wei Xiangzhong. Application Progress of Hot Melt Extrusion Technology in Sustained/ Controlled Release Drug Delivery System [J]. World Clinical Drugs, 2016, 37 (08): 556-562.
About the author:
Sha Luo, a Chinese medicine researcher and developer, now works in a large domestic drug R&D company, devoting himself to the R&D of new drugs of traditional Chinese medicines.
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