Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6 months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs.     

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

Thermal processing technologies continue to gain interest in pharmaceutical manufacturing. However, the types and grades of polymers that can be utilized in common thermal processing technologies, such as hot-melt extrusion (HME), are often limited by thermal or rheological factors. The objectives of the present study were to compare and contrast two thermal processing methods, HME and KinetiSol® Dispersing (KSD), and investigate the influence of polymer type, polymer molecular weight, and drug loading on the ability to produce amorphous solid dispersions (ASDs) containing the model compound griseofulvin (GRIS). Dispersions were analyzed by a variety of imaging, solid-state, thermal, and solution-state techniques. Dispersions were prepared by both HME and KSD using polyvinylpyrrolidone (PVP) K17 or hydroxypropyl methylcellulose (HPMC) E5. Dispersions were only prepared by KSD using higher molecular weight grades of HPMC and PVP, as these could not be extruded under the conditions selected. Powder X-ray diffraction (PXRD) analysis showed that dispersions prepared by HME were amorphous at 10% and 20% drug load; however, it showed significant crystallinity at 40% drug load. PXRD analysis of KSD samples showed all formulations and drug loads to be amorphous with the exception of trace crystallinity seen in PVP K17 and PVP K30 samples at 40% drug load. These results were further supported by other analytical techniques. KSD produced amorphous dispersions at higher drug loads than could be prepared by HME, as well as with higher molecular weight polymers that were not processable by HME, due to its higher rate of shear and torque output.     

Bioavailability of oral drugs and the methods for its improvement

Recent studies in nanotechnology resulted in the development of novel formulations with improved bioavailability. This is especially important for oral administered drugs as the most convenient formulations for administration to patients. The review considers processes occurring in the gastro-intestinal (GI) tract during oral administration of drugs. The increase of bioavailability of the drug may be achieved through designing novel formulations according to the specific drug properties. These include capsules that release pharmaceutical agents at various parts of the GI tract, floating systems that prolong the presence of the drug in stomach, maximally dispersed forms containing surface-active soluble polymers or micelles that carry poor-soluble drugs inside their non-polar core, agents that facilitate tight junction opening, such as caprate and chitosan, and lipid-based formulations. The own data show the stimulating influence of phospholipid nanoparticles on peroral absorption of the drug, indomethacin, in rats and on passage of transport marker and drugs through Caco-2 cell monolayer in vitro. The review summarizes current understanding of factors that influence the bioavailability of the oral drug formulations, currently used models for pharmacokinetic studies, and various approaches to developing novel pharmaceutical formulations that increase the bioavailability of the drugs.     

Bioavailability of silymarin flavonolignans: drug formulations and biotransformation

Over the past years, great advances have been made on the development of novel delivery systems for bioactive natural compounds, in parallel to their structural modification via chemical, chemo-enzymatic and enzymatic methodologies. These approaches give rise to novel formulations and derivatives that often display advantages over the parental molecule, such as enhanced bioavailability and pharmacological activity, due to improved dissolution and stability. Silymarin components suffer from poor solubility in water and lipid media and their resorption in the intestine is rather limited. Moreover, silybin undergoes intensive Phase II metabolism and is rapidly excreted in bile and urine, leading to low therapeutic efficacy. This work aims to present the current status of available silymarin formulations, and to highlight successful efforts for the biotransformation of its constituent flavonolignans towards the synthesis of novel derivatives. Herein, various pharmaceutical formulations that aim at the bioavailability improvement of these fascinating phytochemicals, i.e., liposomes, phytosomes, self-microemulsifying drug delivery systems, solid dispersions systems, dripping pills, nanosuspensions, floating tablets, and micronization, are reviewed. Silybin (semi)synthetic derivatives prepared by chemical or enzymatic methods, such as fatty acid conjugates, silybin bishemisuccinate, silybin glycosides, silybin sulfates, silybinic acid, and 2,3-dehydrosilybin, are also discussed in detail. Additionally, this work attempts to direct the attention towards the pharmacological implications of optically pure silybin A and silybin B and their biotransformation reactions, both Phase I and II, in relation to bioavailability.     

Twin Screw Extruders as Continuous Mixers for Thermal Processing: a Technical and Historical Perspective

Developed approximately 100 years ago for natural rubber/plastics applications, processes via twin screw extrusion (TSE) now generate some of the most cutting-edge drug delivery systems available. After 25 or so years of usage in pharmaceutical environments, it has become evident why TSE processing offers significant advantages as compared to other manufacturing techniques. The well-characterized nature of the TSE process lends itself to ease of scale-up and process optimization while also affording the benefits of continuous manufacturing. Interestingly, the evolution of twin screw extrusion for pharmaceutical products has followed a similar path as previously trodden by plastics processing pioneers. Almost every plastic has been processed at some stage in the manufacturing train on a twin screw extruder, which is utilized to mix materials together to impart desired properties into a final part. The evolution of processing via TSEs since the early/mid 1900s is recounted for plastics and also for pharmaceuticals from the late 1980s until today. The similarities are apparent. The basic theory and development of continuous mixing via corotating and counterrotating TSEs for plastics and drug is also described. The similarities between plastics and pharmaceutical applications are striking. The superior mixing characteristics inherent with a TSE have allowed this device to dominate other continuous mixers and spurred intensive development efforts and experimentation that spawned highly engineered formulations for the commodity and high-tech plastic products we use every day. Today, twin screw extrusion is a battle hardened, well-proven, manufacturing process that has been validated in 24-h/day industrial settings. The same thing is happening today with new extrusion technologies being applied to advanced drug delivery systems to facilitate commodity, targeted, and alternative delivery systems. It seems that the “extrusion evolution” will continue for wide-ranging pharmaceutical products.     

Recent Advances in Lipid Nanoparticle Formulations with Solid Matrix for Oral Drug Delivery

Lipid nanoparticles based on solid matrix have emerged as potential drug carriers to improve gastrointestinal (GI) absorption and oral bioavailability of several drugs, especially lipophilic compounds. These formulations may also be used for sustained drug release. Solid lipid nanoparticle (SLN) and the newer generation lipid nanoparticle, nanostructured lipid carrier (NLC), have been studied for their capability as oral drug carriers. Biodegradable, biocompatible, and physiological lipids are generally used to prepare these nanoparticles. Hence, toxicity problems related with the polymeric nanoparticles can be minimized. Furthermore, stability of the formulations might increase than other liquid nano-carriers due to the solid matrix of these lipid nanoparticles. These nanoparticles can be produced by different formulation techniques. Scaling up of the production process from lab scale to industrial scale can be easily achieved. Reasonably high drug encapsulation efficiency of the nanoparticles was documented. Oral absorption and bioavailability of several drugs were improved after oral administration of the drug-loaded SLNs or NLCs. In this review, pros and cons, different formulation and characterization techniques, drug incorporation models, GI absorption and oral bioavailability enhancement mechanisms, stability and storage condition of the formulations, and recent advances in oral delivery of the lipid nanoparticles based on solid matrix will be discussed.     

Rat Palatability Study for Taste Assessment of Caffeine Citrate Formulation Prepared via Hot-Melt Extrusion Technology

Developing a pediatric oral formulation with an age-appropriate dosage form and taste masking of naturally bitter active pharmaceutical ingredients (APIs) are key challenges for formulation scientists. Several techniques are used for taste masking of bitter APIs to improve formulation palatability; however, not all the techniques are applicable to pediatric dosage forms because of the limitations on the kind and concentration of the excipients that can be used. Hot-melt extrusion (HME) technology is used successfully for taste masking of bitter APIs and overcomes some of the limitations of the existing taste-masking techniques. Likewise, analytical taste assessment is an important quality control parameter evaluated by several in vivo and in vitro methods, such as the human taste panel, electrophysiological methods, electronic sensor, and animal preference tests to aid in selecting a taste-masked formulation. However, the most appropriate in vivo method to assess the taste-masking efficacy of pediatric formulations remains unknown because it is not known to what extent the human taste panel/electronic tongue can predict the palatability in the pediatric patients. The purpose of this study was to develop taste-masked caffeine citrate extrudates via HME and to demonstrate the wide applicability of a single bottle-test rat model to record and compare the volume consumed of the taste-masked solutions to that of the pure API. Thus, this rat model can be considered as a low-cost alternative taste-assessment method to the most commonly used expensive human taste panel/electronic tongue method for pediatric formulations.     

Miniaturization in Pharmaceutical Extrusion Technology: Feeding as a Challenge of Downscaling

In recent years, extrusion technology has shifted the focus of pharmaceutical research due to versatile applications like pelletization, bioavailability improvement or manipulation of solid-state properties of drugs, continuous granulation, and the development of novel solid dosage forms. Meanwhile, a major effort has been devoted to the miniaturization of equipment in pharmaceutical extrusion technology, particularly with regard to the requirements of the development of new chemical entities and formulations. In the present study, a lab-scale twin-screw extruder was investigated in order to determine the limitations imposed by the feeding systems. The wet extrusion process was considered as challenging because both a powder and a liquid feeder have to be considered. Initially, the accuracy and uniformity of the powder and liquid feeder were tested independently of the extrusion process. After modification of the powder feeder, both feeders were investigated in conjunction with extrusion. Based on this, an optimization of the liquid feeder was required and completed. Both feeder modifications reduced the variability of the moisture content in the extrudates 10-fold. This led to a reliable small-scale extrusion process.     

环糊精及其衍生物在多肽/蛋白质类药物非注射给药体系中的应用

目前,多肽/蛋白质类药物多数需要采用注射剂型给药以确保其生物利用度。开发易于给药、病人顺应性高以及治疗费用更低的非注射剂型是非常有意义的。然而,多肽/蛋白质类药物直接进行非注射给药的生物利用度通常非常低,需要制备具有设计功能的载药系统,例如加入不同比例的酶抑制剂、吸收促进剂等以提高生物利用度。环糊精及其衍生物由于其能与客体分子形成包合物的特性,以及对粘膜的促渗透作用等,在多肽/蛋白质药物的非注射给药系统中获得了日益广泛的应用。综述了近年来环糊精及其衍生物在多肽/蛋白质类药物非注射给药体系中的应用情况。     

Zein as a Pharmaceutical Excipient in Oral Solid Dosage Forms: State of the Art and Future Perspectives

Zein is the main storage protein of corn and it has several industrial applications. Mainly in the last 10–15 years, zein has emerged as a potential pharmaceutical excipient with unique features. Zein is a natural, biocompatible and biodegradable material produced from renewable sources. It is insoluble, yet due to its amphiphilic nature, it has self-assembling properties, which have been exploited for the formation of micromicroparticle and nanoparticle and films. Moreover, zein can hydrate so it has been used in swellable matrices for controlled drug release. Other pharmaceutical applications of zein in oral drug delivery include its incorporation in solid dispersions of poorly soluble drugs and in colonic drug delivery systems. This review describes the features of zein significant for its use as a pharmaceutical excipient for oral drug delivery, and it summaries the literature relevant to macroscopic zein-based oral dosage forms, i.e. tablets, capsules, beads and powders. Particular attention is paid to the most novel formulations and applications of zein. Moreover, gaps of knowledge as well as possible venues for future investigations on zein are highlighted.     

Lipid-based vehicle for oral drug delivery

With an increasing number of lipophilic drugs under development, homolipids and heterolipids have gained renewed interests as excipients for oral drug delivery systems. Oral administration has many advantages for chronic drug therapy. It is relatively safe, convenient for the patient and allows self administration. This article is not intended to review the broad area of lipid-based vehicle for oral drug delivery comprehensively. The rationale behind choosing lipids materials for pharmaceutical dosage forms and their applications is discussed. It also comments on the methods for monitoring the physicochemical properties of vehicles and formulations and describes a range of pharmacopoeial excipients suitable for these purposes. The excipients selected here are pharmacopoeial in European Pharmacopoeia 4th Ed., United States Pharmacopoeia 24th Ed./National Formulary 19th Ed. and Japanese Pharmacopoeia 13th Ed. or are drafted in Pharmaeuropa and Pharmacopoeial Forum. Widening availability of lipidic excipients with specific characteristics offer flexibility of application with respect to improving the bioavailability of poorly water-soluble drugs and manipulating release profiles.     

Acid-mediated Lipinski’s second rule: application to drug design and targeting in cancer

With a predicted 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm by 2015, and a current death toll of 1 out of 8 deaths worldwide, improving treatment and/or drug design is an essential focus of cancer research. Multi-drug resistance is the leading cause of chemotherapeutic failure, and delivery of anticancer drugs to the inside of cancerous cells is another major challenge. Fifteen years ago, in a completely different field in which improving drug delivery is the objective, the bioavailability of oral compounds, Christopher Lipinski formulated some rules that are still used by the pharmaceutical industry as rules of thumb to improve drug delivery to their target. Although Lipinski’s rules were not formulated to improve delivery of antineoplastic drugs to the inside of cancer cells, it is interesting to note that the problems are similar. On the basis of the strong similarity between the fields, we discuss how they can be connected and how new drug targets can be defined in cancer.     

Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale

The objective of the study was to develop an amorphous solid dispersion (ASD) for an insoluble compound X by hot melt extrusion (HME) process. The focus was to identify material-sparing approaches to develop bioavailable and stable ASD including scale up of HME process using minimal drug. Mixtures of compound X and polymers with and without surfactants or pH modifiers were evaluated by hot stage microscopy (HSM), polarized light microscopy (PLM), and modulated differential scanning calorimetry (mDSC), which enabled systematic selection of ASD components. Formulation blends of compound X with PVP K12 and PVP VA64 polymers were extruded through a 9-mm twin screw mini-extruder. Physical characterization of extrudates by PLM, XRPD, and mDSC indicated formation of single-phase ASD’s. Accelerated stability testing was performed that allowed rapid selection of stable ASD’s and suitable packaging configurations. Dissolution testing by a discriminating two-step non-sink dissolution method showed 70–80% drug release from prototype ASD’s, which was around twofold higher compared to crystalline tablet formulations. The in vivo pharmacokinetic study in dogs showed that bioavailability from ASD of compound X with PVP VA64 was four times higher compared to crystalline tablet formulations. The HME process was scaled up from lab scale to clinical scale using volumetric scale up approach and scale-independent-specific energy parameter. The present study demonstrated systematic development of ASD dosage form and scale up of HME process to clinical scale using minimal drug (～500 g), which allowed successful clinical batch manufacture of enabled formulation within 7 months.     

Beyond traditional therapy: Mucoadhesive polymers as a new frontier in oral cancer management

In recent times mucoadhesive drug delivery systems are gaining popularity in oral cancer. It is a malignancy with high global prevalence. Despite significant advances in cancer therapeutics, improving the prognosis of late-stage oral cancer remains challenging. Targeted therapy using mucoadhesive polymers can improve oral cancer patients' overall outcome by offering enhanced oral mucosa bioavailability, better drug distribution and tissue targeting, and minimizing systemic side effects. Mucoadhesive polymers can also be delivered via different formulations such as tablets, films, patches, gels, and nanoparticles. These polymers can deliver an array of medicines, making them an adaptable drug delivery approach. Drug delivery techniques based on these mucoadhesive polymers are gaining traction and have immense potential as a prospective treatment for late-stage oral cancer. This review examines leading research in mucoadhesive polymers and discusses their potential applications in treating oral cancer.     

Advanced Technologies for Oral Controlled Release: Cyclodextrins for Oral Controlled Release

Cyclodextrins (CDs) are used in oral pharmaceutical formulations, by means of inclusion complexes formation, with the following advantages for the drugs: (1) solubility, dissolution rate, stability, and bioavailability enhancement; (2) to modify the drug release site and/or time profile; and (3) to reduce or prevent gastrointestinal side effects and unpleasant smell or taste, to prevent drug–drug or drug–additive interactions, or even to convert oil and liquid drugs into microcrystalline or amorphous powders. A more recent trend focuses on the use of CDs as nanocarriers, a strategy that aims to design versatile delivery systems that can encapsulate drugs with better physicochemical properties for oral delivery. Thus, the aim of this work was to review the applications of the CDs and their hydrophilic derivatives on the solubility enhancement of poorly water-soluble drugs in order to increase their dissolution rate and get immediate release, as well as their ability to control (to prolong or to delay) the release of drugs from solid dosage forms, either as complexes with the hydrophilic (e.g., as osmotic pumps) and/or hydrophobic CDs. New controlled delivery systems based on nanotechnology carriers (nanoparticles and conjugates) have also been reviewed.     

Silymarin: an insight to its formulation and analytical prospects

Silymarin, a potential phytochemical compound obtained from the seeds of Silybum marianum plant has been used as a hepatoprotective agent for more than a decade. So far, eight active components of silymarin flavonolignans have been identified, among which silibinin has been proven the most active. However, it had poor oral bioavailability due to extensive phase II metabolism, low permeability across intestinal epithelial cells, low aqueous solubility, and rapid excretion in bile and urine. Therefore it becomes necessary to understand all its formulation and analytical aspects from past to present, including all of its possible future prospects. In modern research scenario, nanotization strategies of drugs has served as a potential approach to enhance solubility, bioavailability and to develop a robust formulation. Several approaches have been utilized previously to enhance the solubility and bioavailability of silymarin to provide it a robust strength against physical, chemical, and environmental degradation. Nanoscale formulations such as nanoemulsion, nanosuspension, liposomes, and solid–lipid nanoparticles can be used to enhance solubility and to target them to desired cells with minimum harm to normal cells. However, many other approaches exist such as dendrimers, ceramic nanoparticles, and carbon nanotubes, which serve as a great vehicle in drug delivery to transport medicament at target sites. Therefore, the purpose of this review was to develop a better understanding of the problems associated with silymarin and approaches to overcome the difficulties to develop a better and stable formulation for food and pharmaceutical applications.     

Carrier-mediated delivery of peptidic drugs for cancer therapy

Protein and peptide drugs are used for treatment of a variety of ailments. However, their wider use has been hindered by issues such as poor bioavailability in vivo and the cost involved in producing these drugs. This review discusses the various carrier-mediated methods used for delivery of peptide and protein drugs, with emphasis on liposomal and microspherical drug delivery systems. A brief look at the types of peptidic drugs currently in use clinically, and a brief discourse on several novel ideas for better protein delivery systems for cancer therapy is included.     

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME

Hypromellose is a hydrophilic polymer widely used in immediate- and modified-release oral pharmaceutical dosage forms. However, currently available grades of hypromellose are difficult, if not impossible, to process by hot melt extrusion (HME) because of their high glass transition temperature, high melt viscosity, and low degradation temperature. To overcome these challenges, a modified grade of hypromellose, AFFINISOL? HPMC HME, was recently introduced. It has a significantly lower glass transition temperature and melt viscosity as compared to other available grades of hypromellose. The objective of this paper is to assess the extrudability and performance of AFFINISOL? HPMC HME (100LV and 4M) as compared to other widely used polymers in HME, including HPMC 2910 100cP (the currently available hypromellose), Soluplus®, Kollidon® VA 64, and EUDRAGIT® E PO. Formulations containing polymer and carbamazepine (CBZ) were extruded on a co-rotating 16-mm twin-screw extruder, and the effect of temperature, screw speed, and feed rate was investigated. The performance of the solid dispersions was evaluated based on Flory–Huggins modeling and characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Raman spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and dissolution. All formulations extruded well except for HPMC 2910 100cP, which resulted in over-torqueing the extruder (machine overloading because the motor cannot provide efficient energy to rotate the shaft). Among the HME extrudates, only the EUDRAGIT® E PO formulation was crystalline as confirmed by DSC, XRD, and Raman, which agreed with predictions from Flory–Huggins modeling. Dissolution testing was conducted under both sink and non-sink conditions. Sink dissolution testing in neutral media revealed that amorphous CBZ in the HME extrudates completely dissolved within 15 min, which was much more rapid than the time for complete dissolution of bulk CBZ (60 min) and EUDRAGIT® E PO solid dispersion (more than 6 h). Non-sink dissolution in acidic media testing revealed that only CBZ contained in the AFFINISOL? HPMC HME, and EUDRAGIT® E PO solid dispersions rapidly supersaturated after 15 min, reaching a twofold drug concentration compared to the CBZ equilibrium solubility. In summary, AFFINISOL? HPMC HME 100LV and AFFINISOL? HPMC HME 4M are useful in the pharmaceutical HME process to increase wetting and dissolution properties of poorly water-soluble drugs like CBZ.     

Nanomaterials for ocular drug delivery

Efficient drug delivery to the eye remains a challenging task for pharmaceutical scientists. Due to the various anatomical barriers and the clearance mechanisms prevailing in the eye, conventional drug delivery systems, such as eye drop solutions, suffer from low bioavailability. More invasive methods, such as intravitreal injections and implants, cause adverse effects in the eye. Recently, an increasing number of scientists have turned to nanomaterial-based drug delivery systems to address the challenges faced by conventional methods. This paper highlights recent applications of various nanomaterials, such as polymeric micelles, hydrogels, liposomes, niosomes, dendrimers, and cyclodextrins as ocular drug delivery systems to enhance the bioavailability of ocular therapeutic agents.