Current Drug Delivery - Volume 18, Issue 4, 2021

Severe Acute Respiratory Syndrome Coronavirus 2 has spread rapidly since its discovery in December 2019 in the Chinese province of Hubei, reaching this day all the continents. This scourge is, unfortunately, in lineage with various dangerous outbreaks such as Ebola, Cholera, Spanish flu, American seasonal flu. Until today, the best solution for the moment remains prevention (Social distancing, hand disinfection, use of masks, partial or total sanitary containment, etc.); there is also the emergence of drug treatment (research and development, clinical trials, use on patients). Recent reviews emphasized the role of membrane lipids in the infectivity mechanism of SARS-COV-2. Cholesterol-rich parts of cell membranes serve as docking places of host cells for the viruses. Coronavirus 2 is a member of a virus family with lipid envelope that fuses with host cell through endocytosis, internalizing its components in the cell. In vitro cell models have shown that depletion of cholesterol by cyclodextrin, and particularly methyl beta cyclodextrin disturb the host cell membrane lipid composition this way, reducing the attachment of the virus to the protein receptors. This review aims to summarize the state of the art of research concerning the use of cyclodextrin or its complexes as a potential treatment against this new virus and update work already published.

Hot Melt Extrusion (HME) is a continuous pharmaceutical manufacturing process that has been extensively investigated for solubility improvement and taste masking of active pharmaceutical ingredients. Recently, it is being explored for its application in 3D printing. 3D printing of pharmaceuticals allows flexibility of dosage form design, customization of dosage form for personalized therapy and the possibility of complex designs with the inclusion of multiple actives in a single unit dosage form. Fused Deposition Modeling (FDM) is a 3D printing technique with a variety of applications in pharmaceutical dosage form development. FDM process requires a polymer filament as the starting material that can be obtained by hot melt extrusion. Recent reports suggest enormous applications of a combination of hot melt extrusion and FDM technology in 3D printing of pharmaceuticals and need to be investigated further. This review in detail describes the HME process, along with its application in 3D printing. The review also summarizes the published reports on the application of HME coupled with 3D printing technology in drug delivery.

Vesicular systems have many advantages like prolonging the existence of the drug in the systemic circulation, minimizing the undesirable side-effects and helping the active moieties to reach their target sites using the carriers. However, the main drawback related to transdermal delivery is to cross stratum corneum, which can be overcome by the utilization of novel carrier systems e.g., transfersomes, which are ultra-deformable carrier systems composed of phospholipid (phosphatidylcholine) and edge activators (surfactants). Edge activators are responsible for the flexibility of the bilayer membranes of transfersomes. Different edge activators used in transfersomes include tween, span, bile salts (sodium cholate and sodium deoxycholate) and dipotassium glycyrrhizinate. These activators decrease the interfacial tension, thereby, increasing the deformability of the carrier system. Transfersomes can encapsulate both hydrophilic and hydrophobic drugs into a vesicular structure, which consists of one or more concentric bilayers. Due to the elastic nature of transfersomes, they can easily cross the natural physiological barriers i.e., skin and deliver the drug to its active site. The main benefit of using transfersomes as a carrier is the delivery of macromolecules through the skin by non-invasive route thereby increasing the patient’s compliance. The transfersomal formulations can be used in the treatment of ocular diseases, alopecia, vulvovaginal candidiasis, osteoporosis, atopic dermatitis, tumor, leishmaniasis. It is also used in the delivery of growth hormones, anaesthesia, insulin, proteins, and herbal drugs. This review also focuses on the patents and clinical studies for various transfersomal products.

Background and Objective: Topical therapy is ineffective in the case of Musculoskeletal Disorders (MSD) as it is not able to maintain therapeutic levels of the drug in the affected joint due to its inability to surpass the dermal circulation and penetrate into deeper tissues. One of the approaches to enhance deep tissue penetration of drugs is to increase drug delivery much above the dermal clearance. The objective of the present work was to formulate negatively charged Deformable Liposomes (DL) of Diclofenac Sodium (DS) using biosurfactants and target the same to the synovial fluid by application of iontophoresis. Methods: Deformable liposomes loaded with diclofenac sodium were formulated and characterized for surface morphology, particle size distribution, zeta potential and entrapment efficiency. In vitro permeation of the diclofenac from aqueous solution, conventional liposomes, and deformable liposomes under iontophoresis was performed using Franz diffusion cells and compared to passive control. Intraarticular microdialysis was carried out to determine the time course of drug concentration in the synovial fluid at the knee-joint region of the hind limb in Sprague Dawley rats. Results: The vesicles were found to display a high entrapment (> 60%) and possess a negative zeta potential lower than -30 mV. The size of the vesicles was varied from 112.41 ± 1.42 nm and 154.6 ± 3.22 nm, demonstrated good stability on the application of iontophoresis. The iontophoretic flux values for the DS aqueous solution, conventional liposomes and deformable liposomal formulation were found to be 7.55 ± 0.42, 16.75±1.77and 44.01 ± 3.47 μg/ cm² h^-1, respectively. Deformable liposomes were found to display an enhancement of 5.83 fold compared to passive control. Iontophoresis was found to enhance the availability of DS deformable liposomes (0.56 ± 0.08 μg.h/ml) in the synovial fluid by nearly 2-fold over passive delivery (0.29 ± 0.05 μg.h/ml). Conclusion: Results obtained indicate that iontophoretic mediated transport of deformable liposomes could improve the regional bioavailability of diclofenac sodium to the synovial joints, an efficient mode for treating MSD in the elderly.

Background: In clinical treatment, it is difficult to carry out effective bone tissue transplantation and anti-inflammatory treatment at the same time due to bone defects and osteomyelitis where the tissue is contaminated or infected. As a downstream target of TNF-α, NF-ΚB has an inhibition effect on the proliferation and differentiation of cells surrounding the lesion. As a negative effect, it leads to a reduction in bone growth and development. Methods: In this study, the small molecule NBD polypeptide and bone conduction matrix Sr-CaS are microspheres, formed to prepare Sr-CaS, NBD drug-loaded sustained-release microspheres in order to achieve a Sr-CaS/NBD peptide drug-loaded sustained release microsphere scaffold material (SP-Sr-CaS/NBD). We prepared the microspheres and optimized the production process to obtain particles with stable morphological properties and sustained release properties. Result: In vitro experiments demonstrated that SP-Sr-CaS/NBD could reduce TNF-α-induced cell growth inhibition, caspase-3 activity and NF-ΚB transcriptional activation as the function of continuous NBD peptide dosing regimen. Conclusion: Also, the introduction of the Sr-CaS matrix potentiates microspheres to promote cell proliferation and provides a basis to become a promising 3D bone scaffold material in the future.

Background: Overcoming the skin barrier to achieve the transdermal penetration of drugs across the Stratum Corneum (SC) remains a significant challenge. Our previous study showed that Fu’s Cupping Therapy (FCT) contributes to the transdermal enhancement and percutaneous absorption rate of representative drugs and improves their clinical effects. This work evaluated the transdermal enhancement effect of FCT on drugs with different Molecular Weights (MW). Methods: We investigated the enhancements in the transdermal penetration of eight types of model drugs through the skin of BALB/c-nu mice and Sprague Dawley rats using Franz diffusion devices. In addition, 3% azone, 5% azone, 3% peppermint oil, and 5% peppermint oil were used as penetration enhancers to study the transdermal behaviour of these drugs. Results: Our results showed that the BALB/c-nu mouse skin was the best transdermal media, and the optimal time for FCT was 10 min. Compared with other penetration enhancers, FCT exerted a significantly improved effect on enhancing the percutaneous penetration of the selected log(P)- model drugs in addition to the two large MW drugs (ginsenoside Rg1 and notoginsenoside R1). Statistical analysis revealed that the relationship between the log(P) of various model drugs and the permeability coefficient [log(Pcm)] of the FCT group was log(Pcm)=0.080(log(P))2-0.136 (log(P))-0.282. Conclusion: FCT may be used as a novel method for enhancing physical penetration and thus effectively promoting the transdermal absorption of drugs and might lay a foundation for future research on drug transdermal technology.

Background: Solid Dispersions (SDs) have been extensively used to increase the dissolution of poorly water-soluble drugs. However, there are few studies exploring SDs properties that must be considered during tablet development, like tabletability. Poorly water-soluble drugs with poor compression properties and high therapeutic doses, like gemfibrozil, are an additional challenge in the production of SDs-based tablets. Objective: This study evaluates the applicability of SDs to improve both tabletability and dissolution rate of gemfibrozil. A SD-based tablet formulation was also proposed. Methods: SDs were prepared by ball milling, using hydroxypropyl methylcellulose (HPMC) as a carrier, according to a 2³ factorial design. The formulation variables were gemfibrozil:HPMC ratio, milling speed, and milling time. The response in the factorial analysis was the tensile strength of the compacted SDs. Dissolution rate and solid-state characterization of SDs were also performed. Results: SDs showed simultaneous drug dissolution enhancement and improved tabletability when compared to corresponding physical mixtures and gemfibrozil. The main variable influencing drug dissolution and tabletability was the gemfibrozil:HPMC ratio. Tablets containing gemfibrozil- HPMC-SD (1:0.250 w/w) and croscarmellose sodium showed fast and complete drug release, while those containing the same SD and sodium starch glycolate exhibited poor drug release due to their prolonged disintegration time. Conclusion: SDs proved to be effective for simultaneously improving tabletability and dissolution profile of gemfibrozil. Tablets containing gemfibrozil-HPMC-SD and croscarmellose sodium as disintegrating agent showed improved drug release and good mechanical strength, demonstrating the potential of HPMC-based SDs to simultaneously overcome the poor dissolution and tabletability properties of this drug.

Background: Poor dissolution of Etodolac is one of the major challenges in achieving the desired therapeutic effect in oral therapy. Objective: This study aimed to assess the potential of the liquisolid compact technique in increasing the rate of dissolution of Etodolac and thus its bioavailability. Methods: Liquisolid compacts were prepared using PEG 400, Avicel PH-200 and Aerosil 200 as non-volatile liquid, carrier and coating material, respectively. The optimisation was carried out by applying a 32 full factorial design using Design expert software 11.0.3.0 to examine the effects of independent variables (load factor and carrier: coating ratio) on dependent variables (angle of repose and % cumulative drug release at 30 min [Q 30 min]). Assessment of bioavailability was based on a pharmacokinetic study on rabbits and pharmacodynamics evaluation on rats, respectively. Results: The formulation M3 was identified as the optimised formulation based on the better flow (lower angle of repose) and a higher rate of dissolution (Q 30 min >95%). The higher dissolution rate could be due to conversion of Etodolac into an amorphous molecularly dispersed state, availability of larger surface area, enhancement of aqueous solubility and enhanced wetting of drug particles. Studies with DSC, XRD, and SEM verified the transformation of Etodolac from crystalline to amorphous state, a key factor responsible for improving the dissolution rate. The pharmacokinetic profile of M3 was prominent, demonstrating higher absorption of Etodolac in comparison to oral suspension and immediate-release conventional tablets in rabbits. Liquisolid formulation exhibited a 27% increment in paw thickness as compared to 57% and 46% increments for oral suspension and immediate-release conventional tablets, respectively, after 7 hrs in the carrageenan-induced paw model in rats. Conclusion: The results indicated the liquisolid compact technique to be a promising strategy to enhance the bioavailability of Etodolac.

Background: Essential oils are poor aqueous solubility and high volatility compounds. The encapsulation of essential oils with Cyclodextrins (CDs) can protect them from adverse environmental conditions and improve their stability. Therefore, increasing the functional capabilities of essential oils when they were used as additives in pharmaceutical and food systems. Additionally, the release of active compounds is an important issue. However, there were few studies about the effect of different CDs on the release of drugs after encapsulation. Therefore, the information on the study of release models is considerably limited.

Objective: This study aimed to (i) characterize the physico-chemical properties and release behavior of myrcene encapsulated in the four different shell matrices of α-CD, β-CD, γ-CD and 2-hydroxypropyl-β- cyclodextrin (HP-β-CD), which were selected from the perspective of stability, and (ii) determine the release mechanism of myrcene in Inclusion Complexes (ICs).

Methods: ICs of myrcene and four CDs were prepared by freeze-drying. The physico-chemical properties of ICs were fully characterized by laser diffraction particle size analyzer, Scanning Electron Microscope (SEM), Fourier-Transform Infrared spectroscopy (FT-IR) and Differential Scanning Calorimeter (DSC). The release behaviors of ICs at 50, 60, 70 and 80 °C were determined and described by zeroorder or first-order kinetics with the Henderson-Pabis, Peppas, Avrami and Page mathematical models. Moreover, the possible binding modes of ICs were identified with molecular modelling technique.

Results: Firstly, the structure of Particle Size Distribution (PSD), FT-IR, DSC and SEM showed that (i) CDs could effectively encapsulate the myrcene molecules, and (ii) the release kinetics were well simulated by Avrami and Page models. Secondly, the release rates of the ICs experienced an unsteady state in the early stage, and gradually became almost constants period after 20 hours. Except that the release of myrcene in γ-CD/myrcene belonged to the first-order kinetic, the release models of the remaining three ICs belonged to diffusion mode. Thirdly, the calculated binding energies of the optimized structures for α-CD/myrcene, β-CD/myrcene, γ-CD/myrcene, and HP-β-CD/myrcene ICs were −4.28, −3.82, −4.04, and −3.72 kcal/mol, respectively. Finally, the encapsulation of myrcene with α-CD and β-CD was preferable according to the stability and release characteristics.

Conclusion: The encapsulation of myrcene was profoundly affected by the type of CDs, and the stability could be improved by complexation with suitable CDs. The binding behavior between guest and CD molecules, and the release profile of the guest molecules could be effectively explained by the kinetics parameters and molecular modelling. This study can provide an effective basis and guide for screening suitable shell matrices.

Objective: The objective of the current research work was to prepare chewable tablets having Acacia catechu extract useful for mouth ulcers using a 3² factorial design. Methods: Acacia catechu heartwood extract was prepared using a reported method with some modifications. The extract was characterized using TLC against the catechin marker. Then, drug-excipient interaction studies were carried out. The mixture of drug and excipients was evaluated for pre-compression parameters. With the application of 3² factorial design, chewable tablets were prepared using direct compression technique. Prepared tablets were evaluated for post-compression parameters. Results: In vitro drug release study of the developed formulations was investigated both in intact and crushed form of tablets. Based on the in vitro performance, the best formulations were selected (F6, F7 & F8 from intact and F1, F5 & F9 from the crushed group) and subjected to various kinetic models and evaluated for Chewing Difficulty Index (CDI). Conclusion: The overall results revealed that the formulated chewable tablets complied with the standards and exhibited the satisfactory performance in terms of drug release, chewing difficulty index and other related parameters.

Background: Supersaturable SMEDDS, a versatile dosage form, was investigated for improving the biopharmaceutical attributes and eradicating the food effect of poorly water soluble drug efavirenz. Objective: The present research pursues the development of efavirenz loaded Supersaturable Self- Microemulsifying Drug Delivery System (SS SMEDDS) for improving biopharmaceutical performance. Methods: Preformulation studies were carried out to determine the optimized range of lipid excipients to develop stable supersaturated SMEDDS (ST SMEDDS). The SS SMEDD formulation was prepared by adding hydroxypropyl methylcellulose as a polymeric precipitation inhibitor. The developed SS SMEDDS were evaluated for supersaturation behavior by performing in vitro supersaturation studies and molecular simulations by in silico docking. Dissolution was performed in biorelevant media to simulate fed/fasted conditions in gastrointestinal regions. Absorption behavior was determined through in vivo pharmacokinetics approach. Results: The optimized ST SMEDDS formulation containing Maisine® CC, Tween 80 and Transcutol-P exhibited thermodynamic stability with quick rate of emulsification. The optimized SS SMEDDS containing suitable polymeric precipitation inhibitor exhibited enhanced efavirenz concentration in in vitro supersaturation test. The theoretical simulations by molecular docking revealed strong intermolecular interactions with a docking score of -3.004 KJ/mol. The dissolution performance of marketed product in biorelevant dissolution media inferred the existence of food effect in the dissolution of efavirenz. However, in SS SMEDDS, no significant differences in drug release behavior under different fasted/fed conditions signify that the food effect was neutralized. In vivo pharmacokinetics revealed a significant increase in the absorption profile of efavirenz from SS SMEDDS than that of ST SMEDDS and marketed product. Conclusion: The designed delivery system indicated promising results in developing an effectual EFV formulation for HIV treatment.