Current Pharmaceutical Design - Volume 23, Issue 2, 2017

Background: Bioactive compounds from various natural sources have been attracting more and more attention, owing to their broad diversity of functionalities and availabilities. However, many of the bioactive compounds often exist at an extremely low concentration in a mixture so that massive harvesting is needed to obtain sufficient amounts for their practical usage. Thus, effective fractionation or separation technologies are essential for the screening and production of the bioactive compound products. The applicatons of conventional processes such as extraction, distillation and lyophilisation, etc. may be tedious, have high energy consumption or cause denature or degradation of the bioactive compounds. Membrane separation processes operate at ambient temperature, without the need for heating and therefore with less energy consumption. The “cold” separation technology also prevents the possible degradation of the bioactive compounds. The separation process is mainly physical and both fractions (permeate and retentate) of the membrane processes may be recovered. Thus, using membrane separation technology is a promising approach to concentrate and separate bioactive compounds. Methods: A comprehensive survey of membrane operations used for the separation of bioactive compounds is conducted. The available and established membrane separation processes are introduced and reviewed. Results: The most frequently used membrane processes are the pressure driven ones, including microfiltration (MF), ultrafiltration (UF) and nanofiltration (NF). They are applied either individually as a single sieve or in combination as an integrated membrane array to meet the different requirements in the separation of bioactive compounds. Other new membrane processes with multiple functions have also been developed and employed for the separation or fractionation of bioactive compounds. The hybrid electrodialysis (ED)-UF membrane process, for example has been used to provide a solution for the separation of biomolecules with similar molecular weights but different surface electrical properties. In contrast, the affinity membrane technology is shown to have the advantages of increasing the separation efficiency at low operational pressures through selectively adsorbing bioactive compounds during the filtration process. Conclusion: Individual membranes or membrane arrays are effectively used to separate bioactive compounds or achieve multiple fractionation of them with different molecule weights or sizes. Pressure driven membrane processes are highly efficient and widely used. Membrane fouling, especially irreversible organic and biological fouling, is the inevitable problem. Multifunctional membranes and affinity membranes provide the possibility of effectively separating bioactive compounds that are similar in sizes but different in other physical and chemical properties. Surface modification methods are of great potential to increase membrane separation efficiency as well as reduce the problem of membrane fouling. Developing membranes and optimizing the operational parameters specifically for the applications of separation of various bioactive compounds should be taken as an important part of ongoing or future membrane research in this field.

Background: This review aims to present the relevant background information and current research status in concentration of polyphenols using membrane technologies. The potential implementation of membrane separation to bioactive compounds like soluble phenolics from aqueous and organic solvent solutions is gaining increasing interest in the recent years. This review does not pretend to cover the abundant published literature on the subject, but to be representative for the observed tendencies in membrane processes applications for concentration of polyphenols derived from natural products. The first part of the article includes general information regarding the polyphenols and the traditional methods for their separation (such as: thin layer chromatography; paper chromatography; gas chromatography; high performance liquid chromatography; capillary electrophoresis), while the second part presents a review of different membrane processes applied for concentration of polyphenols. Three main sources for such implementations are discussed: (1) aqueous or organic solvent extracts from plant material, (2) fruits, and (3) recovery of polyphenols from industrial waste liquids. A diversity of membrane processes are considered in a large scope of implementations ranging from lab-scale studies to pilot and semiindustrial scale operations. Conclusion: Membrane technology is an excellent candidate to make a paradigm shift in biological active compounds fractionation/separation processes. Presented results clearly demonstrate that membrane processes are of great advantages over traditionally used methods; however, characterization of separated polyphenols has to be improved. Most of citied authors concentrated their investigation only on the total amount of polyphenols determination. Exhaustive studies including: antioxidant activities, retention index, total soluble solids, or volume reduction factor, have been only carried out by a few authors.

Background: Membrane technologies are of increasing importance in a variety of separation and purification applications involving liquid phases and gaseous mixtures. Although the most widely used applications at this time are in water treatment including desalination, there are many applications in chemical, food, healthcare, paper and petrochemical industries. This brief review is concerned with existing and emerging applications of various membrane technologies in the pharmaceutical and biopharmaceutical industry. Methods: The goal of this review article is to identify important membrane processes and techniques which are being used or proposed to be used in the pharmaceutical and biopharmaceutical operations. How novel membrane processes can be useful for delivery of crystalline/particulate drugs is also of interest. Results: Membrane separation technologies are extensively used in downstream processes for bio-pharmaceutical separation and purification operations via microfiltration, ultrafiltration and diafiltration. Also the new technique of membrane chromatography allows efficient purification of monoclonal antibodies. Membrane filtration techniques of reverse osmosis and nanofiltration are being combined with bioreactors and advanced oxidation processes to treat wastewaters from pharmaceutical plants. Nanofiltration with organic solvent-stable membranes can implement solvent exchange and catalyst recovery during organic solvent-based drug synthesis of pharmaceutical compounds/intermediates. Membranes in the form of hollow fibers can be conveniently used to implement crystallization of pharmaceutical compounds. The novel crystallization methods of solid hollow fiber cooling crystallizer (SHFCC) and porous hollow fiber anti-solvent crystallization (PHFAC) are being developed to provide efficient methods for continuous production of polymer-coated drug crystals in the area of drug delivery. Conclusion: This brief review provides a general introduction to various applications of membrane technologies in the pharmaceutical/biopharmaceutical industry with special emphasis on novel membrane techniques for pharmaceutical applications. The method of coating a drug particle with a polymer using the SHFCC method is stable and ready for scale-up for operation over an extended period.

In biological systems, recognition at molecular level is governed by chiral interactions. Therefore, optical isomers have very different effect in natural systems. For example, one can have beneficial effect while the other can be very harmful. For these reasons, chiral drugs nowadays are mainly admitted in the optically pure form. Given these requirements, it is clear why demand for chiral drugs has grown dramatically and the singleenantiomer drug segment has become an important part of the overall pharmaceutical market. As a consequence, the development of new chiral separation techniques is a very hot topic in both academic research and industrial innovation. Membrane bioreactors have proven their feasibility in the production of optically pure enantiomers by combining enantiospecific biochemical reactions with mass transport through membranes. The principles and the applications of enantioselective membrane bioreactors in kinetic resolution for pharmaceutical applications will be discussed. Various membrane bioreactors configurations and operation mode will be illustrated. The type of enzymes utilized to produce chiral drugs or their intermediates will be also reported. Multistep syntheses, conducted in sequential reactions catalysed by spatially aligned biocatalysts, as promising technology for the synthesis of fine chemicals will be highlighted.

Background: Bio-nanomaterials assembled into nanomembrane entities are actively studied to circumvent the uncontrollable list of shortcomings of conventional delivery systems: low water solubility, unfavorable stability, short circulation time in plasma, rapid clearance from the human body, poor bioavailability, non-specific toxicity against normal tissue and cells, low cellular uptake and susceptibility to enzyme degradation. Basically, these nanoentities enable to exploit the therapeutic value of many promising biomolecules and drugs (B), controlling the mass transport of B at a certain rate or even on demand if a stimulus is applied. The large surface-to-volume ratio of bio-nanomaterials as well as their tunable properties enable to increase the biocompatibility, bioavailability, solubility and permeability of many unique B which are otherwise difficult to deliver. Results: This review paper will focus on the last advances of bio-nanomaterials applied as nanomembranes in biomolecule and drug delivery, as well as their more remarkable properties and applications in biomedicine. Conclusion: New advances have been drastically established in the production of smart nanomembranes that alter their own structure and function in response to the environment. These new insights have been used for the production of smart drug delivery nanomembranes. These nanomembranes entities have the potential to revolutionize the biomedicine but there are still some shortcomings to address in order to translate the laboratory production to the clinic.

Background: Polymer-based systems are attractive in drug delivery and regenerative medicine due to the possibility of tailoring their properties and functions to a specific application. Methods: The present review provides several examples of molecularly engineered polymer systems, including stimuli responsive polymers and supramolecular polymers. Results: The advent of controlled polymerization techniques has enabled the preparation of polymers with controlled molecular weight and well-defined architecture. By using these techniques coupled to orthogonal chemical modification reactions, polymers can be molecularly engineered to incorporate functional groups able to respond to small changes in the local environment or to a specific biological signal. This review highlights the properties and applications of stimuli-responsive systems and polymer therapeutics, such as polymer-drug conjugates, polymer-protein conjugates, polymersomes, and hyperbranched systems. The applications of polymeric membranes in regenerative medicine are also discussed. Conclusion: The examples presented in this review suggest that the combination of membranes with polymers that are molecularly engineered to respond to specific biological functions could be relevant in the field of regenerative medicine.

Background: In conventional drug delivery, the drug concentration in the blood raises once the drug taken, and then peaks and declines. Since each drug has a level above which it is toxic and another level below which it is ineffective, the drug concentration in a patient at a particular time depends on compliance with the prescribed routine. Methods: To achieve more effective efficacy and fewer side effects of drugs, the drug carriers with desirable dosing and controllable release property of drugs are highly desired. Stimuli-responsive capsules with smart gating membranes or hydrogel-based membranes as capsule shells are ideal candidates. The smart capsule membranes enable efficient encapsulation of drugs within the large inner volume, and the responsive gating membranes or hydrogel-based membranes could control the release rate of encapsulated drugs in responding to environmental stimuli. The trigger stimuli could be either artificial or natural ones corresponding to specific diseases, such as temperature, pH, glucose concentration, specific ion, light, and magnetic field. Results: This review highlights the recent development in stimuli-responsive capsule membranes for controlled release in pharmaceutical applications, including two types of stimuli-responsive capsule membranes with different architectures for on/off release and burst release, which can achieve potential uses of case-dependent on/off release and burst release. Conclusion: The preponderances of the smart capsule membranes are that the capsules are with controllable inner space for drug vehicles with desired dose and stimuli-responsive membrane as shell to release drugs at a desired site and/or moment. However, the actual difficulties for the stimuli-responsive capsule membrane systems to go before they can be applied widely in the biomedical fields are discussed. The future works should focus on the improvements of biocompatibility, biodegradability and stimuli-responsiveness of the capsule membranes, easy and scalable fabrication techniques with further decrease of the capsule size for more efficient in vivo applications, and the diversification of the multi-compartmental capsule architectures with multi-stimuli-responsive characteristics for controlled release.

Nowadays, the rational design of particles is an important issue in the development of pharmaceutical medicaments. Advances in manufacturing methods are required to design new pharmaceutical particles with target properties in terms of particle size, particle size distribution, structure and functional activity. Membrane emulsification is emerging as a promising tool for the production of emulsions and solidified particles with tailored properties in many fields. In this review, the current use of membrane emulsification in the production of pharmaceutical particles is highlighted. Membrane emulsification devices designed for small-scale testing as well as membrane-based methods suitable for large-scale production are discussed. A special emphasis is put on the important factors that contribute to the encapsulation efficiency and drug loading. The most recent studies about the utilization of the membrane emulsification for preparing particles as drug delivery systems for anticancer, proteins/peptide, lipophilic and hydrophilic bioactive drugs are reviewed.

In drug development, in vitro human model systems are absolutely essential prior to the clinical trials, considering the increasing number of chemical compounds in need of testing, and, keeping in mind that animals cannot predict all the adverse human health effects and reactions, due to the species-specific differences in metabolic pathways. The liver plays a central role in the clearance and biotransformation of chemicals and xenobiotics. In vitro liver model systems by using highly differentiated human cells could have a great impact in preclinical trials. Membrane biohybrid systems constituted of human hepatocytes and micro- and nano-structured membranes, represent valuable tools for studying drug metabolism and toxicity. Membranes act as an extracellular matrix for the adhesion of hepatocytes, and compartmentalise them in a well-defined physical and chemical microenvironment with high selectivity. Advanced 3-D tissue cultures are furthermore achieved by using membrane bioreactors (MBR), which ensure the continuous perfusion of cells protecting them from shear stress. MBRs with different configurations allow the culturing of cells at high density and under closely monitored high perfusion, similarly to the natural liver. These devices that promote the long-term maintenance and differentiation of primary human hepatocytes with preserved liver specific functions can be employed in drug testing for prolonged exposure to chemical compounds and for assessing repeated-dose toxicity. The use of primary human hepatocytes in MBRs is the only system providing a faster and more cost-effective method of analysis for the prediction of in vitro human drug metabolism and enzyme induction alternative and/or complementary to the animal experimentation. In this paper, in vitro models for studying drug metabolism and toxicity as advanced biohybrid membrane systems and MBRs will be reviewed.

Background: Estrogens and their synthetic analogues are widely used as pharmaceuticals. Upon oral administration these drugs are eventually excreted via urine. The persistence of these pharmaceuticals and inefficient removal by water treatment lead to accumulation in surface water and effluents with negative effects for aquatic life and human health. Methods: In this study, the uptake of estradiol by a combined magnetic ion exchange resin - ultrafiltration process (MIEX-UF) was investigated. This is a relatively common process used in drinking water treatment for the removal of natural organic matter. However, uptake of micropollutants, such as steroidal pharmaceuticals, may occur as a side effect of water treatment due to the high affinity for polymeric materials. To elucidate the mechanism governing estradiol partitioning between water, resin and membrane, the influence of different parameters, such as pH, humic acid concentration and membrane molecular-weight-cut-off (MWCO) was studied. Results: Humic acid concentration and pH affected estradiol uptake most. At pH 11 the most significant increase of estradiol uptake was observed for MIEX-UF process (30 ng/g corresponding to 80%) compared with individual UF (17 ng/g corresponding to 12%). The presence of humic acid slightly reduced estradiol uptake at pH 11 (about 55%) due to competition for the ion exchange binding sites. Conclusion: Results demonstrated that the uptake of estradiol, which is amongst the most potent EDCs detected in surface water, in the MIEX-UF process can reach significant quantities (30 ng/g of resin) leading to uncontrolled accumulation of this micropollutant during drinking water treatment. This study gives a novel contribution in the understanding the mechanism of the unanticipated accumulation of pharmaceuticals, such as estradiol, in the drinking water treatment process.