Mesoporous Systems for Drug Delivery: Introduction, Literature Review, and Loading Methods

 1. Could you please write a proposal about this project Introduction literature review on mesoporous systems for drug delivery, for solubility enhancement, and specifically on the loading methods

2. Introduction and literature review on mesoporous systems for drug delivery, for solubility enhancement, and specifically on the loading methods (Spray dying, rotary evaporation and solvent impregnation)

The common mesoporous materials entail those from alumina and silica, which have similar mesoporous. Mesoporous silica is processed from inorganic materials which are produced from sodium silicate using a surfactant. The synthesis process of these materials often depends on the porous structure and other parameters such as source, morphology, ion strength, temperature, and other variables. These underlying conditions have a direct impact on the structure, surface area, and pore size and wall thickness (Kierys et al. 2019).

The pore size modulation of mesoporous silica materials has offered an avenue for usage on bulky molecules such as drugs and enzymes and other compounds such as dyes. In this avenue, the underlying adsorption processes are initiated through covalent bonding, cross-linking, and entrapment (Xu, Riilonen, and Lehto, 2013). Immobilization is reliant on the biomolecule dimensions, such as the hydrophilic and hydrophobic nature.  The immobilization of these compounds is processed through porous silica that has a high surface area and high pore diameter than that of the adsorbate. The silanol groups on the mesoporous silica surface have a soft favour immobilization on the biomolecule or any electrostatic interactions.  

The mesoporous natures of silica materials have attracted great attention in therapeutic avenues. They have been employed towards designing and formation of drug delivery systems (26-8), and other diagnostic uses. These materials are successful when employed in the fabrication of polymer composites (Bagheri et al. 2018). However, a challenge, in this case, is to obtain a homogeneous dispersion within the polymer matrix since they exhibit a stronger tendency for agglomeration (Liu et al. 2011; Supova et al. 2013). Mesoporous silica polymers have been identified as a key aspect of being a carrier for drugs and other complicated pore systems and chemical characters. The nature in which they are prepared makes them an essential aspect as they can be applied as drug carriers for oral matrix systems. The method of combining the silica particles in the polymer microspheres has been an essential aspect since there is the avoidance of free nanoparticles in the formulation process. In this way, the toxicity levels of the mesoporous silica are mitigated. The mesoporous silica added advantage is the nature of the diameter which is within range hence cannot pass through the blood-brain barrier or aspect of penetrating the cells (Kierys et al. 2019).

Synthesis Process of Mesoporous Silica Materials

Usage and utilization of mesoporous materials are exploited in support and catalytic processes. In recent years, they have been viewed as a promising component in catalysis reactions due to the ability to tailor the properties of the catalytic processes (Ting et al. 2018). They are used in combination with other elements that can modify their acidity. Some of the chemical elements which have been incorporated to aid this entail Aluminum, Ta, Zr, Nb, or Ti. The inclusion process of these heteroatoms needs to be modulated as they can affect the condensation of the porous silica, which can affect the disorder's structures already present. The increase of the heteroatom can also affect the texture properties as they can block the porous structures partially. Mesoporous silica has higher levels of being dispersed in small metallic forms or on surfaces of the porous structures (White et al. 2009).

Polymer reinforcement has been undertaken on mesoporous silica. They have great potential to improve the addictive, chemical, biological, and thermo-mechanical aspects of polymer-based materials (Maleki et al. 2014). The porosity of the polymer materials offers an avenue to accommodate high levels of polymer chains. Further, various composites have been employed, such as the polyethylene oxide and styrene-butadiene rubber/MCM-41(Maiti, Basak, Srivastava, and Jasra 2016). Further, porous silica has been employed as a hard template. The porous nature is efficient in its application as a synthesizer of carbon structures. Porous structures are impregnated with a carbon source, and then it undergoes pyrolysis to obtain a carbon matrix (Cecilia, Moreno and Retuerto 2019).

Mesoporous silica materials have been extensively employed in the fabrication process of polymer composites (Lee and Yoo 2016). Challenge has been how to obtain the composite with the mesoporous particles homogenously through dispersion in the polymer matrix as the inorganic particles have shown strong agglomerate tendencies. Polymer materials have been demonstrated to be very attractive as drug carriers as they have complex pores and unique chemical character. The formation of the polymers in the form of microspheres enables them to be used as drug carriers in oral drug mechanisms. This avenue is more promising as it embeds aspects of silica mesoporous making it free from nanoparticles. In this way, the overall toxicity is mitigated successfully. The formed diameter of the mesoporous polymer is in average micrometer range hence reduces penetration in blood and cell wall pores. The application of synthesized mesoporous fillers in the template molecules has been viewed interestingly. The mesoporous pore template molecules are not accessed by the monomers in the synthesis process. In this case, they are free polymer in the composite phase. Further, the template has double groups of hydrophilic and hydrophobic. This presence in the system can synthesize facilitation, thus mixing the mesoporous particles to obtain homogeneous mesoporous dispersion in the polymer matrix (Kierys et al. 2019).

Applications of Mesoporous Silica Materials

In the recent decade, the mesoporous silica nanoparticles have gained traction due to their positive effect on large surface areas, pore size, and high volume due to their nature as molecules. The key potential benefits entails the ability to have the large surface area and pore volume which beneficial for drug loading mechanism, flexible pore structures which can release drugs easily, a modifiable surface which are essential in facilitated and targeting drug delivery to improve therapeutic effects, positive hear conversion ability, smooth biocompatibility, supramolecular stacking ability of p–p which is essential in loading high capacity drugs and unique properties for optic abilities. In this way, mesoporous silica is an essential avenue for drug delivery mechanisms and biomedical utilization (Uthappa et al. 2019).

Drug delivery systems based on the mesoporous silica carriers entail four categories. The first category is the surface modification drug delivery system. The carbon polymer framework of the mesoporous carbon silica is formed from high thermal temperatures (Liu et al., 2013). The original forms are highly hydrophobic. In modifying them to hydrophilic nature, oxidization using strong acids is usually undertaken, thus creating functional groups (Zhu et al. 2012). The acidic oxidization can form functional groups that could be further modified to other forms of polymer, grafting, and application in diagnostic imaging.

Immediate release drug delivery systems are viewed as the most convenient and easily administered drug. The clinical application process of hydrophobic drugs has not been exploited thoroughly due to poor solubility and bioavailability in the GI tract. In the advent of the immediate release delivery mechanism, these drugs have employed mesoporous materials being used. These mesoporous polymers have low density, high porosity, and a strong ability to undergo adsorption processes. According to Liu et al. (2016), usage of Eu3þ/Gd3þ-EDTA used to improve oral bioavailability. Drug loading efficiency in this way of the carboxylated HMC can reach 73.6% of the solvent evaporation levels and about 47.8% adsorption levels.

Zhang et al. (2013b) demonstrated that carboxylated mesoporous carbon could improve the solubility and dissolution rate of the CAR, thus improving the overall bioavailability after intake orally. The drug state was amorphous, and after being loaded into the nanoscale, the equilibrium solubility and the dissolution rate were improved immensely compared to the crystal drug state.  

Particle size and pore size have a greater influence on the drug delivery system. Particles of mesoporous sizes have a greater impact on how drugs are released. According to Zhang et al. (2013a), various mesoporous carbon display a unique behavior as compared to the model drug simvastatin. Results have demonstrated that increased release is improved with a reduction of the size of particles due to reduced diffusion distance covered.  

Loading Methods for Mesoporous Systems

Pore size dissolution rate could be enhanced by enlarging the pore diameters as they have a hindrance to the diffusion rate. Practical studies by Zhao et al. (2012a), has demonstrated that fabrication of mesoporous size of carbon used for loading in drug celecoxib to improve the dissolution levels and increase bioavailability rates. The results of this demonstration showed that the dissolution period is reduced (Eleftheriadis et al. 2016).

Sustained release drug delivery method is an approach that can extend therapeutic effect by releasing the encapsulated drugs slowly over a long period, thus reducing the frequency of administration, drug concentration stabilization, reduction in side effects, and achievement of better compliance of patients. Using the sustained release drug delivery methods, three categories have emerged; pore structure. This avenue is achieved with the regulation of the morphology structure of the carriers, which have a crucial effect on the rate of release of drugs loaded. The second category entails interaction association between the mesoporous polymers and the loaded drugs. Sustained levels of drug release are attained through utilizing the strong interaction of force, i.e., the supramolecular hydrophobic interactions and electrostatic force. The third avenue is using the diffusion effect; in the modified carbon polymers, the grafted portion can provide a hindrance to the drug release, thus maintaining drug release sustenance (Zhao et al. 2017).

The overall texture and the physical appearance of the mesoporous silica carbons and polymer have a great influence on the loaded drugs. For sustaining this release rate, there is a need for designing of unconnected pore structure and small pore sizes in the process through there is an alteration on the pre structure and channel length. There is an established relationship on the drug load and particle size nanocarrier, which is often proportional to the overall length of the channel pore. In a study by Zhao et al. (2012a), comparing the mesoporous structures and load of lovastatin, profile release showed that its release from the fabricated fibrous ordered mesoporous carbon having two-dimension and longer channel pores are slow. Making a comparison with the conventional mesoporous carbon, hollow mesoporous structures can sustain drug release based on their mesoporous nature and hollow innate cavity. Higher drug load ability is an interesting feature of the hollow mesoporous, which has accessible channels in the shell acting as a drug depth. Further, the release of drugs in the hollow mesoporous carbon in a thicker shell is often slower based on the long diffusion distance, which signifies long-distance traveling during the diffusion time of the drug molecules into the nearby medium (Zhao et al. 2017).

Spray Drying

Interaction force occurring between the loaded drug and the vehicle can have a delaying effect on the drug release hence could serve a potential benefit to a sustained drug delivery system. The carbon framework can produce supramolecular stacking having aromatic drug molecules to attain the drug release. Zhu et al. (2012) developed a small-diameter 90nm transmembrane as a delivery vehicle for doxorubicin drugs. The mesoporous demonstrated a high loading ability related to the hydrophobic interactions between the drug and the mesoporous carbon. The Doxorubicin demonstrated a sustained release in the acidic state and physiological pH caused by strong interaction between the mesoporous carbon and the drug. This dependency of the doxorubicin drug and the mesoporous carbon showed a reduced toxicity level in the normal tissue in the circulation process in the body (Chen et al. 2014).

Diffusion hindrance effect on the mesoporous polymer modification on the interaction between the carriers and drugs showed an increase in diffusion rates, thus creating a high impact level drug release. More focus thus is directed towards modification of mesoporous polymers and carbons due to their role in sustained drug delivery approach. They can demonstrate small pores, high adsorption ability, and elevated drug loading power compared to other drug carriers hence enhancing the dispersion of drugs and regulating its release.

Controlled drug delivery systems entail stimuli responsiveness, targeted drug delivery system and combined controlled and targeted drug delivery systems. In a bid to control unwarranted drug release, which could serve drug loss and adverse side effects, mesoporous based systems have been developed to achieve a stimuli response release. These novel avenues are achieved through the modification of the gatekeepers using covalent bonds which prevent drug molecules leakage from the drug delivery system unless they are exposed to redox, pH, and temperature among other catalysts. The pH response controlled drug delivery system is the most common prevalent form between diseases. Redox method is another used avenue in which it triggers the drug release through stimulus based on the glutathione concentration in both extra and intracellular fluids (Zhao et al. 2017).

Targeted drug delivery system uses a nano-drug delivery system that can achieve a targeted drug delivery without any form of leakage in the transportation process and release the drug at specific tumour sites in the body. Targeted drug delivery system is divided into; passive and active forms of delivery. Passive delivery takes place with preferential access to target sites based on nano-size particles. The active strategy enables the modified carrier to offer specificity. Combined methods of controlled and targeted delivery systems have shown an increased interest in the carbon base multidimensional system, this delivers target location can release the during load in a more controlled manner to increase the cellular intake of the slow premature release before sending to the target site.  

Rotary Evaporation

The fundamental critical aspect of drug properties involves oral drug dosages that utilises their solubility and permeability to be absorbed in the body. Drugs need to dissolve in the GI to ensure the absorption process in the systematic circulation pathway. The formulation of low soluble drugs often faces the greatest danger as they are poorly absorbed and exhibit low bioavailability in the body.

Low solubility problems have been addressed through avenues of solubilisation techniques such as size reduction, salt formation, and solid dispersion methods among others. In the industrial process, solid dispersion is commonly preferred as they are low costs and easy to undertake. This technique utilization a process referred to as amorphization where crystalline drugs are transformed into high energy through amorphous forms that illustrate high solubility (Zografi and Newman 2015). 

In this process, the mesoporous materials such as silica and other polymers have been exploited in this process of drug amorphization as they can achieve partial drug confinement of molecules in the nanopore structures (Garcia-Bennett and Feiler 2014). Mesoporous carriers have been shown to offer flexibility concerning the spore sizes and inherent surface areas (Choudhari et al. 2014). Mesoporous silica is critical in the bioavailability process of soluble drugs.

Drug loading methods are often carried out using three key methods they entail melting, physical adsorption and solvent evaporation. According to Niu et al. (2013), mesoporous carbon with the surface area of 1175 m2/g can improve the solubility and dissolution rates of the hydrophobic fenofibrate. Various loading methods have demonstrated that there is a greater influence on the drug molecules' status in the carrier and the in vitro dissolution. Melting methods has been observed to achieve high efficiency of drugs that can penetrate the PRS and drug molecules. In the physical adsorption method, the mesoporous polymer is soaked in the drug solutions, in this way drug molecules can penetrate the pre channels until attaining equilibrium. The drug leaded mesoporous carbon is then collected using centrifugation. The solvent evaporation approach utilizes the combined effort of physical adsorption and rapid evaporation process. There is a high chance of achieving a higher LE% in comparison to the other adsorption methods and less drug bonding compared to the melting methods. The release of the in vitro process showed the dissolution rates of the FFB loaded with mesoporous was highly enhanced as they diffuse ion in the dissolution medium easily.

Solvent Impregnation

Particle size and pore size play a fundamental role in drug loading methods. Mesoporous silica particles size has been shown to have a great effect on drug release rates (Zhang et al.2013a), showed that synthesis of mesoporous silica having various sizes as compared to drug simvastatin, indicated that there is an elevated level of release with small particle thus reducing where the drug reaction timing, that is, rate of release of the drug can be set from before and covered during the diffusion process. The pore size has a critical role to play during the dissolution process as it relates to lowering diffusion hindrance. Usage of fabricated fibrous order mesoporous carbon during the loading process has been demonstrated to improve the dissolution rate of celecoxib drug and increases the rate of bioavailability. In this regards mesoporous have distinct features compared to other forms of drug delivery systems. High surface area and volume pore ensure that there is a high rate of encapsulation of high payload drugs. This aided by the nanoscale pore channels which maintain the amorphous state allowing easier dissolution rate (Eleftheriadis et al. 2016).

Solvent-free approaches entail physical mixing, heating, co-milling, and usage of supercritical carbon dioxide. This approach offers a critical advantage in that they do not need to be checked for residual solvent in drugs and have low impacts on the environment. Solvent-based approaches offer an avenue for drug armophosation in the mesoporous silica. Various critical issues influence the loading of drugs into the mesoporous silica. These factors entail solvent type, load drug, surface area and the volume of the mesoporous pore. Solvent-based approaches such as spry drying have an effort of producing a drug load of mesoporous silica in a highly efficient manner as compeer to solvent-free approaches (Choudhari et al. 2014). High loadings of drugs above 30% (w/w) can end with an incomplete armophosation, leaving small particles of drug crystals on the exterior surfaces. Molecules of drugs can be absorbed into the mesoporous silica as multi monolayer’s as per the dimension of drug molecules, surface area and the size of the pores.

An investigation by Dening and Taylor (2018) on ritonavir loading of mesoporous at various drug loads ranging from 25-150% surface coverage, results demonstrated that drug release declined as the loaded drug rose. In this view, it is necessary to investigate the overall impact of the loading of drugs above the monolayer surface through overloading aspects through the thermal behaviour of the drugs within the mesoporous layer. Combination of mesoporous silica and hypromellose acetate succinate has been investigated and results demonstrated that it promotes amorphization of celecoxib, however, an in-depth study is still needed to investigate on the precipitation inhibitors to assess on how low soluble drugs having different chemical features can be beneficial (Lain’e et al. 2016).

Polymer Composites

The aim of this study thus is to assess the overall impact of drug release ability into the mesoporous carriers, loading ability, stability and thermal behaviour, dissolution, and solubility of the load drugs. Further, key fundamental objectives were to assess the release profiles of the load drugs in the mesoporous silica and studying the morphology nature of the loaded drugs within the mesoporous polymers. The overall benefit of this study is to establish the link between the drug loads and formulation aspects touching on efficiency, release aspects and drug nature in the mesoporous carriers.

To obtain felodipine (FELO), Discovery Fine Chemicals situated in Dorset, United Kingdom will be approached. Mesosol, which is a mesoporous carrier and is made up of cellulose acetate butyrate, will be taken from in-house and will have an average pore size of 20 nm. Sigma-Aldrich in Dorset, UK was approached to purchase sodium lauryl sulfate, sodium phosphate dibasic, and sodium phosphate monobasic. Fisher Scientific in Loughborough, UK was approached to get ethanol and acetone. The production of deionized water will be ensured by Milli-Q Integral system present in Hertfordshire, UK.

Drug load theory calculation will be undertaken following an assumption that molecules of drugs can absorb the surface area of mesoporous silica particles through a packing geometry able to increase the bonding process of silica surface and molecules of drugs to maximize the surface area (Dening, and Taylor 2018). The drug load calculation will be undertaken based on the following formula derived by Dening and Taylor (2018) to obtain the drug load, to obtain the monolayer adsorption in the mesoporous silica;

SSA: Specific surface area of the mesoporous silica

MW: Molecular weight of the model drug

SAM: Maximum projected contact surface area

NA: Avogadro number = 6.022X1023

Spray Drying of Microparticles and Characterisation

Monodisperse beads were framed from the antecedent arrangement by a small scale fluidic vaporized spout framework with a diameter distance across of 75 µm, bringing about beads of around 150 µm in measurement. The arrangement was taken care of into a standard steel repository with dehumidified instrument air to drive the fluid to stream through the spout. The stream was separated by aggravation from vibrating piezoceramics. Bead arrangement was checked utilizing a computerized SLR (Nikon D90) with a speed light (Nikon SB-400) and miniaturized scale focal point (AF Micro-Nikkor 60 mm f/2.8D). Bead dividing was advanced by means of modification of recurrence and time of incitement of the piezoelectric spout under perception utilizing rapid photography. Because of the effective contact between drying air and monodisperse beads in a solitary stream, each and every bead was changed over to a molecule on coordinated premise. The splash drying gulf temperature was 160 °C. The molecule assortment productivity was >70% by weight, and gathered particles were then stove dried medium-term at 100 °C. The surfactant layout was then evacuated through direct calcination in static air condition at 550 °C for 5 hours with a 2 °C min-1 incline. To create carbonaceous materials, the carbonisation was done in a nitrogen domain at 648 K. The morphology, surface region, pore structure, and long range requesting of mesostructures of microparticles were dissected.

Catalytic Processes

SBA-15, MCM-41 or FS particles (6 mg/mL) were scattered in CH3)2CO or ethanol tranquilize arrangements (2 mg/mL) utilizing a water shower sonicator for 15 minutes. The subsequent suspensions (target tranquilize stacking was set at 25 % w/w, SM, Section 2.3) were attractively blended medium-term in screw-topped vials. An aliquot of 1 mL of the scattering was centrifuged and tranquilize was measured in the supernatant with UV spectrophotometry. The top was evacuated so as to permit dissipation of solvents while blending to acquire KAZ3 stacked mesoporous silica particles in a set structure.

In an average blend, 6.4 g of F127 was disintegrated in an answer containing 32.0 g of ethanol and 0.3 g of HCl (37 wt%) under attractive mixing, in a 40 oC H2O shower. At that point, 2.8 g of sucrose in 10 g of H2O was blended in with 8.32 g of TEOS (for the underlying silica carbon proportion for Si66C33), and added to the layout F127 arrangement. The blend was consistently mixed in the 40C water shower for another 1 h. From that point onward, the forerunner arrangement was moved into a 1 L round base cup, which was associated to a rotavap, half inundated in a water shower of 40 oC. After beginning pivot at 200 rpm, the weight was diminished under clearing, which incited quick dissolvable evacuation and frothing. In 10 min, the weight diminished to ca. 100 mbar, the inner mass of the cup was secured with the silica-sucrose-F127 gel also, not any more generous beads were seen at the condenser channel of the rotavap. The pivot and departure were proceeded for another 1 h. The complete dissolvable dissipation and self-assembly time is definitely abbreviated contrasted with that of TFEISA (normally ca. 20 h).2,23 The as-framed frothed gel was at that point restored at 160 oC for 24 h in air, trailed by pyrolysis at 400 (or 550 oC) to give the composite Si66C33Rot-400 (or Si66C33Rot550). SO3H bunches were effectively acquainted with produce Si66C33Rot-400-SO3H and Si66C33Rot-550-SO3H by sulfonation in a shut autoclave utilizing accumulated H2SO4 at 150 oC for 15 h,2,15 managing SO3H site thickness of 0.31 and 0.23 mmol/g, individually. Sulfonation of the silica-carbon nanocomposite had no effect on the basic properties because of the nearness of the inflexible silicate structure in the composite, as announced previously.

The morphology of stacked and emptied silica particles was researched by methods for checking electron microscopy (SEM, Carl Zeiss EVO HD-15, Oberkochen, Germany). Particles were mounted onto twofold cement layer on an aluminum stub.

The examples were gold-covered utilizing particle sputtering gadget (Edwards S150B, West Sussex, UK) and checked at a quickening voltage of 10 kV.

The properties of the thermal samples will be characterized by the DSC instrument. Each sample will be weighed at the equivalence of 1 mg of Felodopine to the Tzero low mass aluminum with heating at a range f 50-300 oC and scanning rates of 10 oC/min in a nitrogen flow rate of 50 mL/min.

The drug load surface containing mesoporous silica will be examined using Philips XL30 FEG using 10 kV in a high vacuum. Before this coating of the samples will be undertaken and coated with gold through a sputter coater. The Electron microscopy scan will be undertaken under power 2000 magnification.

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