Originally, the HME processing was mainly and widely employed in the plastic industry for the preparation of plastic products, and more than half of plastic products such as plastic bags, sheets and pipes are manufactured by this processing (94). The application of hot-melt extrusion in the pharmaceutical industry can be dated back as early as 1971 (95). Since then it has been widely used as a processing method for the preparation of solid dispersions and can be used to modify dissolution rate of drugs (37). In comparison to other solid dispersion preparation methods, such as solvent evaporation based method, HME can be superior in some aspects (38). Firstly, it is a solvent free method in which no organic solvent is required in preparation. The involvement of organic solvent can be problematic in terms of environmental pollution and high cost to recover.
Secondly, it is a continuous single-step processing method which can be a highly efficient in preparing samples. Thirdly, scale up could be relatively easy. The disadvantage of hot melt extrusion is the potential thermal degradation of heat-sensitive drugs and polymers in preparation, which restricts the selection of drugs and polymers can be processed by HME. Nevertheless, hot melt extrusion is becoming increasingly popular in preparing solid dispersions in the pharmaceutical industry. The main applications of hot melt extrusion in the pharmaceutical
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industry include fast release formulations, sustained release formulations and special formulation design and they will be discussed in the following sections.
1.5.1 Fast release formulations
Fast release formulations by hot melt extrusion are mainly based on the preparation of amorphous solid dispersions (23, 96-99). By using HME to process drug-polymer mixtures into amorphous solid dispersions, dissolution rate of poorly water-soluble drugs can be significantly enhanced. Itraconazole is a typical BSCⅡ drug with extremely low aqueous solubility (1.8µg/ml in pH 1.2 solution) (100). In one study, itraconazole and hydroxypropylmethyl-cellulose (HPMC) 2910 solid dispersions were prepared by HME and amorphous solid dispersions were confirmed by MTDSC and PXRD with drug loadings of up to 40% (w/w) (101). In this study, drug release of 90%
was achieved after 120min even from 40% (w/w) loading formulation under sink condition (101).
In a very recent study of using hot melt extrusion to improve dissolution performance of ketoprofen, another typical poorly water-soluble drug, hydroxypropylcellulose (HPC) was used (102).
Amorphous solid dispersions were confirmed by DSC and PXRD up to 60% (w/w) drug loading in this study (102). In addition to enhancing the dissolution rate of the drug, the increased drug release rate can also be modified by using HPC with different grades. This was explained in the paper by the different swelling and erosion rates of different grades HPCs (two types of HPCs with the molecular weight of 60000 and 80000, respectively) (102). These successful applications of improving dissolution rates of poorly water-soluble drugs demonstrate that hot melt extrusion is an effective processing method for the enhancement of drug release via the preparation of amorphous solid dispersions.
The fast release mechanism of drugs from solid dispersions has been debatable (39). Two established models have been reported. In the first instance, a valuable contribution was provided by Corrigan in which not only the dissolution rate of the incorporated drug was measured but also the dissolution rate the polymer carrier (PEG) was assessed (103). The author found that the dissolution rate of the drug and the polymer was equivalent, which leads to the suggestion of carrier-controlled drug release whereby the dissolution rate of the drug is controlled by the inert carrier in the solid dispersion. This model was supported by other studies presenting similar results (104, 105). However, adisagreement issue was raised from Lloyd et al by arguing that if dissolution was dominated by the carrier rather than the drug, the physical form of the drug should be irrelevant (106). By examining the release of paracetamol from PEG 6000 solid dispersions, they found that formulations prepared with larger drug size fractions showed a higher drug release rate.
With similar work from other groups, a drug-controlled dissolution was introduced whereby the dissolution rate of the drug is controlled by the drug dissolving and thus physical state of the drug (such as reduced particle size or changed into amorphous) can significantly affect the dissolution (107). Out of the two models, the dominant mechanism of drug release from solid dispersions is
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dependent on whether the drug dissolves in the polymer diffusion layer rapidly in dissolution (carrier-controlled) or not (drug-controlled). The schematic illustration of the two mechanisms is shown in Figure 1.10.
Figure 1.10: Schematic illustration of fast release mechanisms (a: carrier controlled dissolution whereby the drug dissolves into the concentrated carrier layer prior to release; b: drug-controlled dissolution whereby the drug is released effectively intact into the dissolution media) (39).
1.5.2 Modified release formulations
The preparation of solid dispersions, using hot melt extrusion with water insoluble polymeric carriers, may sustain drug release from formulations (108, 109). Miyagawa et al. used twin-screw hot-melt extruder to prepare controlled release diclofenacsodium formulations with different matrices (110). It was found that the dissolution rate can be controlled by adjusting the drug loadings. Recently, a series of studies using hot melt extrusion to prepare sustained release mini-matrices were carried out from the same research group (109, 111). Ethylcellulose was used as the main sustained release matrix in these studies (109, 111). In the first study, it was proved that using xanthamgum with different concentrations and different particle sizes in ethyl-cellulose based formulations, drug release of ibuprofen can be tailored to the required specifications (109). The dissolution of the drug was controlled by diffusion rather than erosion of polymers. Further research from the same group concluded that mechanical parameters including screw design, powder feed rate and screw rotation speed of hot melt extrusion in preparation had no influence on the homogeneity of products and drug release (metoprolol tartrate as model drug) profiles(111).
This may demonstrate that hot melt extrusion is consistent and robust process for the preparation of solid dispersions in controlling drug release (111).
Form these studies, it can be concluded that the controlled release mechanism of a water-soluble drug from hot melt extruded solid dispersion is mainly dependent on the physical properties of the drug and the applied polymer carriers (112). If the polymer is hydrophilic, drug release is controlled by the swelling and erosion of the polymer in dissolution. If the drug is incorporated in
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water-insoluble polymers, such as ethyl-cellulose, drug release is controlled by the diffusion of dissolution media into the matrix and followed by the diffusion of drug molecules through the polymer matrix into the dissolution media (113).
1.5.3 Other applications
In addition to the modification of drug release rate, two other typical applications of hot melt extrusion including the preparation of drug-loaded films and taste masking have been reported (37, 38). Polymeric films containing drugs are usually designed for local drug delivery systems such as transdermal and transmuscoal drug administration. Compared with other time-consuming casting techniques which may involve solvents and have environmental concerns, HME is a viable method for film based formulations (38). The film can be obtained by attaching a special roller unit to the end of the HME and the thickness of the film can be controlled. Film preparation using hot melt extrusion has been reported in articles (114-117). For example, lidocaine was prepared into film formulation by HME using hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC) as matrices (115). In this study, the formation of an amorphous solid dispersion was confirmed by DSC and XRPD (115). A burst drug release at the early stage (to reach the required drug concentration in plasma within short time period) and a sustained drug release at later stage (to maintain the drug concentration in plasma) were achieved in the permeation test using diffusion cell (115).
Taste masking can be obtained through the formation of interaction (such as hydrogen bonding) between bitter drugs and polymer carriers (118). It has also been reported that the unpleasant flavour of the drugs can be masked if drugs can be molecularly dispersed into polymer carries (119). Therefore, hot melt extrusion as an effective preparation process for solid dispersions was introduced for taste masking. A case study reported using HME for the taste masking of paracetamol by formulating the drug with EUDRAGIT® EPO and Kollidon® VA64(120). In-vivo results by patients showed that both polymers can provide a taste masking effect with the drug loading up to 50% (w/w), and Kollidon® VA64 was slightly better (up to 60% w/w). This was likely attributed to the fact that paracetamol was partially crystalline in the EUDRAGIT® EPO melt extrudates whereas although phase separated, paracetamol was still amorphous in Kollidon® VA64 dispersions as confirmed by PXRD. However, in the paper it was not discussed why amorphous solid dispersions showed better taste masking effect than solid dispersions containing crystalline drugs. Nevertheless, the results still demonstrated that using HME as to prepare amorphous solid dispersions was an effective method for taste masking.