Current Drug Delivery - Volume 19, Issue 1, 2022

Hormonal drugs are essential treatment options for some hormone-dependent or hormone- sensitive tumors. The common dosage forms of hormonal drugs have a short half-life. Hence, frequent administration is needed, which results in poor patient compliance. Nevertheless, using drug delivery technology, somatostatin analogues (SSAs) and gonadotropin-releasing hormone (GnRH) analogues are prepared into long-acting formulations that can significantly prolong the action time of these drugs, reducing medication frequency and increasing patient compliance. Such drugs are advantageous when treating acromegaly, gastroenteropancreatic neuroendocrine tumors (GEP-NETs), breast cancer, prostate cancer, and other diseases having a relatively long course. SSAs and GnRH analogues are two typical hormonal drugs, the long-acting formulations of which are essential in clinical practice. This review summarized the preparation methods and clinical application of long-acting formulations in cancer. Further, the action mechanism and new research of SSAs and GnRH analogues were discussed, and suggestions related to the development of long-acting SSAs and GnRH analogues were provided.

Alzheimer’s Disease (AD), a progressive and irreversible neurodegenerative disorder, is the most common form of dementia worldwide. Currently, there is no disease-modifying AD drug, and the development of effective treatments is made even harder by the highly selective nature of the Blood-Brain Barrier (BBB) that allows the passage only of molecules with specific chemicalphysical properties. In this context, nanomedicine and its Nanoparticles (NPs) offer potential solutions to the challenge of AD therapy, in particular, the requirements for i) BBB crossing, ii) multitarget therapy iii) enhancement of pharmacokinetics; and iv) more precise delivery. In addition, the possibility to optimize NP biophysical and biological (i.e. target-specific ligands) properties allows for highly tailored delivery platforms. Preclinical studies have demonstrated that nanotherapeutics provide superior pharmacokinetics and brain uptake than free drugs and, on the other hand, these are also able to mitigate the side-effects of the symptomatic treatments approved by the FDA. Among the plethora of potential AD nanodrugs, multitarget nanotherapeutics are considered the most promising strategy due to their ability to hit simultaneously multiple pathogenic factors, while nano-nutraceuticals are emerging as interesting tools in the treatment/prevention of AD. This review provides a comprehensive overview of nanomedicine in AD therapy, focusing on key optimization of NPs properties, most promising nanotherapeutics in preclinical studies and difficulties that are limiting the efficient translation from bench to bedside.

Background: Exenatide(EXE) is an anti-hyperglycemic agent approved for treating type 2 diabetes by the Food and Drug Administration(FDA). However, twice-daily injection of exenatide is inconvenient for most of the patients. Objective: In this study, biotinylated trimethylated chitosan(Bio-TMC) based nanoparticles were proposed to promote oral absorption of exenatide. Realizing the oral administration of exenatide is very important to alleviate patient suffering and improve patient compliance. Methods: Bio-TMC was synthesized, and the chemical structure was characterized by Fourier transform infrared (FT-IR) spectroscopy and 1H NMR spectroscopy. Nanoparticles were prepared through polyelectrolyte interaction in the presence of sodium Tripolyphosphate (TPP) and hydroxypropyl methylcellulose phthalate (HP-55). Formulations were physically and chemically characterized. In vitro release was investigated in different pH media. In vivo antidiabetic activities of biotin modified and non-biotin modified chitosan were evaluated in db/db mice. Results: EXE-loaded Bio-TMC/HP-55 nanoparticles were spherical in shape with a mean diameter of 156.2 nm and zeta potential of +11.3 mV. The drug loading efficiency and loading content were 52.38% and 2.08%, respectively. In vitro release revealed that EXE-loaded Bio-TMC/HP-55 nanoparticles were released faster in pH 1.2 than pH 6.8 (63.71% VS 50.12%), indicating that nanoparticles have enteric characteristics. Antidiabetic activity study revealed that after oral administration to diabetic mice, the relative pharmacological bioavailability (FPharm%) of the biotin modified nanoparticles was found to be 1.27-fold higher compared to the unmodified ones, and the hypoglycemic effect was also found to be better. Conclusion: Bio-TMC/HP-55 nanoparticles are feasible as oral drug carriers of exenatide and have the potential to be extended to other drugs that are not readily oral, such as monoclonal antibodies, vaccines, genes, etc. These would be beneficial to the pharmaceutical industry. Further research will focus on the biodistribution of Bio-TMC/HP-55 nanoparticles after oral administration.

Introduction: The amentoflavone (AMF) loaded polymeric sub-micron particles were prepared using supercritical antisolvent (SAS) technology with the aim of improving the anticancer activity of AMF. Methods: Zein and phospholipid mixtures composed of Hydrogenated Phosphatidylcholine (HPC) and egg lecithin (EPC) were used as carrier materials and, the effects of carrier composition on the product morphology and drug release behavior were investigated. When the mass ratio of Zein/HPC/ EPC was 7/2/1, the AMF loaded particles were spherical shape and sub-micron sized around 400 nm, with a drug load of 4.3±0.3 w% and entrapment efficacy of 87.8±1.8%. The in vitro drug release assay showed that adding EPC in the wall materials could improve the dispersion stability of the released AMF in an aqueous medium, and the introduction of HPC could accelerate the drug release speed. Results: MTT assay demonstrated that AMF-loaded micron particles have an improved inhibitory effect on A375 cells, whose IC50 was 37.39μg/ml, compared with that of free AMF(130.2μg/ml). Conclusion: It proved that the AMF loaded sub-micron particles prepared by SAS were a prospective strategy to improve the antitumor activity of AMF, and possibly promote the clinical use of AMF preparations.

Background: The combination of photothermal therapy (PTT) and chemotherapy has proven to be a promising strategy for cancer treatment. Various nanomaterials have shown great potential in combination therapy, including gold, graphene oxide, iron oxide, and other nanoparticles. However, their undefinable toxicity in vivo greatly slowed down their development for clinical applications. Objective: The present work aimed to develop a multifunctional nanoparticle for chemo-photothermal therapy composed of acknowledged biocompatible materials. Methods: A novel biocompatible nanoparticle (HIT-NPs) was self-assembled through the intrinsic interaction between D-α-tocopherol Succinate (TOS), human serum albumin (HSA) and indocyanine green (ICG). Doxorubicin (DOX) was then loaded due to the ion pairing between DOX and TOS. The feasibility of combined chemo-photothermal therapy induced by DOX-loaded HIT-NPs was carefully evaluated. Results: In vitro, HIT-NPs showed no cytotoxicity on human normal liver cells (HL-7702 cells) but obvious killing effects on murine breast cancer cells (4T1 cells). The combined chemo-photothermal therapeutic effect on 4T1 cells was successfully obtained. DOX-loaded HIT-NPs could effectively accumulate in 4T1 subcutaneous tumors after intravenous injection, and the tumor temperature rapidly increased under laser exposure, indicating the feasibility of PTT in vivo. Conclusion: The self-assembled HIT-NPs could provide a promising platform for combined chemo- photothermal cancer therapy with full biocompatibility.

Aim: In this work, to improve the solubility and bioavailability of the rosuvastatin (RSV) drug, chitosan-coated mesoporous silica nanoparticles (CS-MSNs) as a drug delivery system were fabricated. Methods: To do this, first MSNs with a maximum specific surface area were synthesized from sodium silicate as silica source and different molar ratios of cethyl trimethylammonium bromide (CTAB) and pluronics (P123, PEO20PPO17PEO20) as surfactants via the sol-gel process. Then, the synthesized MSNs were coated by CS polymer with the help of (3-glycidoxypropyl)methyldiethoxysilane (GPTMS) as a linker between MSNs and CS. Subsequently, the RSV drug was loaded into the synthesized CS-coated MSNs. The products were characterized by different techniques, including X-ray diffraction (XRD), the Brunauer-Emmett-Teller (BET), scanning electron microscopy (SEM), dynamic light scattering (DLS), and Fourier-transform infrared spectroscopy (FTIR). The in vitro drug release profile of the fabricated DDS was evaluated in a typical phosphate-buffered saline (PBS) solution at different pH values (i.e., 4, 6, and 7.4) for 48 h. To assess the cytotoxicity, the viability of the human fibroblast cells exposed to the fabricated DDS was also examined. Results: The results showed that at an optimal molar ratio of P123/CTAB, the amorphous MSNs with a specific surface area of about 1080 m2/g, a pore diameter of 4 nm, a pore volume of 1.1 cm3/g, and an average size of about 30 nm were synthesized. Also, the presence of all the components, including the CS coating and the RSV drug, was confirmed in the structure of the fabricated DDS by FTIR analysis. Due to the pH-responsive feature of the CS coating, the RSV drug release from the fabricated DDS showed a reasonable environmental response; as the pH value of the PBS solution decreased, the degree of drug release increased. Conclusion: The CS coating enhanced the cytotoxicity of the fabricated DDS and led to sustainable drug release behavior, which would provide a beneficial approach for drug delivery technology.

Introduction: Hydrophilic polymers that swell or dissolve in aqueous media can have the potential to prepare controlled/sustained dosage forms for weakly acidic and poorly soluble drugs. Objective: The main objective of this study is to utilize Eudragit^®E100 (EE) and Carbopol^®971P NF (Cp) polymers and their salt forms for the preparation of a once-daily controlled-release matrix tablet for model drug, Ibuprofen (IB). Methods: Combinations of the polymers in their base forms (EE)/(Cp) or in their salt forms (EEHCl/ CpNa) were compressed with (IB) into single layer matrix tablets, or otherwise into bilayer tablets. Dissolution profiles were constructed using three different consecutive stages (pH 1.2, 4.8 and 6.8). Results: It was found that the incorporation of (EEHCl) modified the release rates of (IB) from (Cp) based matrix tablets. However, a major enhancement of (IB) release rates occurred when the polymers were combined in their salt forms in a 1:1 ratio by weight. In addition, a bilayer tablet was prepared wherein a relatively rapidly disintegrating layer composed of polymers salts (EEHCl and CpNa), and a second layer containing only (Cp) polymer in its base form in a 1:2 weight ratio possessed excellent release properties and mechanical strength. Conclusion: It was concluded that the prepared bilayer tablet could be promising for controlling the release rates of (IB) in an extended manner to allow once-daily administration with an improved pH-independent release behavior.

Background: Albendazole (ABZ) is the drug of choice for the treatment of a variety of human and veterinary parasites. However, it has low aqueous solubility and low bioavailability. Cyclodextrins (CD) are pharmaceutical excipients with the ability to modulate the solubilization property of hydrophobic molecules. Objective: The aim of the study was to analyze through in vitro and in silico studies (Autodock Vina software and CycloMolder platform) the formation of inclusion complexes between ABZ, β-cyclodextrin (β-CD) and its derivatives Methyl-β-cyclodextrin (M-β-CD) and Hydroxypropyl-β-cyclodextrin (HP-β-CD). Methods: The most stable inclusion complexes were produced by the kneading method and characterized by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), X-Ray Diffraction (XRD), determination of the ABZ content and in vitro dissolution profile. Results: Molecular modeling revealed that inclusion complexes between HP-β-CD:ABZ (in the proportion 1:1 and 2:1) presented the lowest formation energy and the highest number of intermolecular interactions, showing that the use of more cyclodextrins does not generate gains in the stability of the complex. On the characterization tests, the complexes experimentally obtained by the kneading method demonstrated highly suggestive parameters, including ABZ in HP-β-CD in both molar proportions, suppression of bands in the infrared spectrum, displacement of the drug's melting temperature in DSC, crystallinity halos instead of the characteristic peaks of ABZ crystals in the XRD and a release of more than 80% of ABZ in less than 5 minutes, dissolution efficiency of up to 92%. Conclusion: In silico studies provided a rational selection of the appropriate complexes of cyclodextrin, enabling the elaboration of more targeted complexes, decreasing time and costs for elaboration of new formulations, thereby increasing the oral biodisponibility of ABZ.

Introduction: Metformin, an anti-diabetic drug, has low bioavailability and short biological half-life. Thus, bioavailability enhancement and prolonged release of the drug are highly desirable. In this regard, we aimed to developed gastroretentive nanoparticles made of jackfruit seed starch (JFSS) loaded with metformin. Methods: Developed nanoparticles were optimized for various process variables and were further characterized. Nanoparticles exhibited good results with respect to particle size (244.3 to 612.4 nm), particle size distribution, shape and drug entrapment efficiency (75.8 to 89.2%) with sustained drug release for 24 h and a high buoyancy (89% for F7; formulation made of highest concentration of Jackfruit seed starch prepared at 1000 RPM stirring speed). Results: The hypoglycemic potential of these nanoparticles was tested in nicotinamide streptozocin induced diabetic model, there was a significant reduction in blood glucose level (50% reduction from 4-8 h; p < 0.01) for prolonged period of time (up to 24 h) in comparison to diabetic control and plain metformin solution. Conclusion: The outcome of the study suggested that developed formulations are suitable for gastro- retentive delivery of Metformin in a controlled manner appropriate for a single administration per day.

Introduction: Brucellosis is a zoonotic disease that is prevalent in livestock animals. The bacteria reside inside the macrophage cells of the host. The WHO has endorseda combination treatment therapy for brucellosis against the conventional monotherapy to avoid relapse and resistance. Therefore, we developed nanoparticles incorporating doxycycline and rifampicin in combination. Aim: The aim of the study is to develop polymeric nanoparticles incorporating doxycycline as well as rifampicin and investigate the antibacterial activity of nanoparticles in U937 human macrophage cells infected with B. abortus. Methods: Polymeric nanoparticles were developed by the emulsion-solvent diffusion method, and characterization was performed. Results: The nanoparticles with high entrapment efficiency of both the drugs were developed successfully. Scanning electron microscopy revealed a spherical morphology with a size ranging ~450nm, which can be easily engulfed by the macrophages. Zeta potential confirmed the colloidal stability. Differential scanning calorimetry and X-ray diffraction suggested amorphization of doxycycline and rifampicin in nanoparticles. Fourier transfer infrared spectroscopy could not confirm the interaction of drugs with AOT. In vitro haemolysis study confirmed the safety of nanoparticles (<10%) for IV administration. Further, nanoparticles revealed the sustained release of both drugs, which followed diffusion kinetics. Nanoparticles were found stable for 6 months as per WHO guidelines. The internalization study revealed nanoparticles could be easily uptaken by U-937 human macrophage cells. The efficacy study demonstrated significantly high antibacterial activity of nanoparticles as compared to free drug solution in U937 human macrophages cells infected with Brucella abortus. Conclusion: It can be concluded that the developed nanoparticles entrapping doxycycline and rifampicin combination can be considered as a promising delivery system for enhancing the antibacterial activity against Brucella abortus.

Background: Rutin is available on the market as a topical formulation for the treatment of several conditions, such as internal bleeding, hemorrhoids, and varicose veins. However, these gels have low solubility and limited bioavailability due to their decreased lipid solubility. Objective: In this study, we aimed to synthesize potentially novel lipophilic rutin prodrugs. The suggested library of these rutin prodrugs includes changing the solubility profile to facilitate rutin transport across biological barriers, thereby improving drug delivery through topical application. Methods: Six rutin derivatives were synthesized based on the ester prodrug strategy. The synthesized compounds were formulated as topical ointments, and their permeability via Franz diffusion was measured. An ultraviolet (UV) analytical method was developed in our laboratories to quantify rutin derivatives both as raw materials and in final dosage forms. The analytical method was then validated. Results: The results of Franz diffusion analyses showed that transdermal permeability increased by 10-fold for decaacetylated rutin compared to the other esterified rutins. A simple analytical method for the analysis of the formulated rutin ester was developed and validated. Moreover, the formulated ointment of decaacetylated rutin in our research laboratory was found to be stable under stability accelerated conditions. Synthesis of potentially more lipophilic compounds would yield novel rutin prodrugs suitable for topical formulation. Conclusion: This project provides a synthetic approach for many similar natural products. The research idea and strategy followed in this research project could be adapted by pharmaceutical and herbal establishments.

Aim: The present research work was aimed to formulate fast disintegrating tablets (FDTs) of salbutamol sulphate (SBS) using a combination of a superdisintegrant and a subliming agent, optimize the formulation and evaluate the in vitro performance of the developed FDTs. Materials and Methods: A formulation of SBS FDT was developed using a combination of superdisintegrant - crospovidone and subliming agent - Ammonium Bicarbonate (AB) in which formulation variables, namely levels of crospovidone and Microcrystalline Cellulose (MCC):Mannitol (MNTL) ratio, were evaluated for their effects on the response variables, disintegration time, hardness, friability and wetting time, of the resulting FDTs. By employing Central Composite Design (CCD) methodology, the FDTs were optimized to achieve optimum levels of the formulation factors. Results: The desired optimum condition was obtained at 7.82% crospovidone and 70% of 1.56:1 MCC: MNTL ratio, while maintaining AB at 5% level for aesthetic reasons. Under the optimized conditions, the disintegration time, hardness, friability, and wetting time were 14.57 ± 0.53 sec, 7.17 ± 0.82 kg/cm2, 0.311% and 13.14 ± 0.69 sec, respectively. The experimentally observed responses were found to be in close agreement with the predicted values for the optimized formulation. Moreover, the validity of the obtained optimal point was confirmed by the low magnitude of percent prediction error (< 5%). Conclusion: FDTs of SBS were successfully formulated and optimized using CCD employing a combination of a superdisintegrant and a subliming agent.

Objectives: One of the promising strategies for effective HIV-1 vaccine design involves finding the polyepitope immunogens using T cell epitopes. Methods: Herein, an HIV-1 polyepitope construct (i.e., Nef-Tat-Gp160-P24) comprising of several epitopes from Nef, Tat, Gp160, and P24 proteins was designed. To improve its immunogenicity in BALB/c mice, cell-penetrating peptides (HR9 and MPG for DNA delivery, and LDP-NLS and Cy- LoP-1 for protein transfer), Montanide adjuvant, and heterologous DNA prime/polypeptide boost strategy were used. To compare the immunogenicity, Nef was utilized as a vaccine candidate. The levels of total IgG and its subclasses, cytokines, and Granzyme B were assessed using ELISA. Results: Immunological studies showed that heterologous prime-boost regimens for both antigens could considerably augment the levels of IgG2a, IgG2b, IFN-γ, and Granzyme B directed toward Th1 and CTL immune responses in comparison with homologous prime-boost strategies. The levels of IFN-γ, IL-10, total IgG, IgG1, and IgG2b were drastically higher in groups immunized with Nef-Tat-Gp160-P24 in heterologous prime-boost regimens than those in groups immunized with Nef. Conclusion: The use of the Nef-Tat-Gp160-P24 polyepitope immunogen in heterologous primeboost strategy could generate the mixture of Th1 and Th2 responses directed further toward Th1 response as a hopeful method for improvement of HIV-1 vaccine.

Introduction: Typically, in situ forming implants utilize Poly (lactide- co- glycolide) (PLGA) as carrier and N-methyl-2-pyrrolidone (NMP) as solvent. However, it is essential to develop different carriers to release various drugs in a controlled and sustained manner with economic and safety considerations. Objective: The present study aims to evaluate the in-vitro release of Bupivacaine HCl from in situ forming systems as post-operative local anesthesia. Methods: We used Sucrose acetate isobutyrate (SAIB), PLGA 50:50, and a mixture of them as carriers to compare the release behavior. Besides, the effect of PLGA molecular weight (RG 502H, RG 503H, and RG 504H), solvent type, and solvent concentration on the drug release profile has been evaluated. The formulations were characterized by investigating their in-vitro drug release, rheological properties, solubility, and DSC, in addition to their morphological properties. Furthermore, the Korsmeyer-Peppas and Weibull models were applied to the experimental data. Results revealed that using a mixture of SAIB and PLGA compared to using them solely can extend the Bupivacaine HCl release from 3 days to two weeks. Results: The DSC results demonstrated the compatibility of the mixture by showing a single Tg. The formulation with NMP exhibited a higher burst release and final release in comparison with other solvents by 30% and 96%, respectively. Increasing the solvent concentration from 12% to 32% raised the drug release significantly, which confirmed the larger porosity in the morphology results. From the Korsmeyer-Peppas model, the mechanism of drug release has been predicted to be non-Fickian diffusion.