Current Drug Delivery - Volume 18, Issue 1, 2021

The misuse, abuse, and illicit use of prescription opioid analgesics is a global public health concern. However, there are many viable therapeutic options for the treatment of patients with chronic pain. Both intact and manipulated opioid drug products are abused by various routes such as oral, nasal, and injection, which may lead to overdose, drug addiction, and even death. To combat the abuse of these medications, regulatory agencies and pharmaceutical companies are switching their interest towards developing Abuse Deterrent Formulations (ADFs), with the intent to deter the abuse of opioid products to a maximum extent. There are several manufacturing strategies implemented in an attempt to develop ADFs. An example includes matrix tablets of high molecular weight polymers such as polyethylene oxide. The scalable and continuous manufacturing techniques, such as Hot-Melt Extrusion (HME), is increasingly accepted by pharmaceutical companies to advance the development and manufacturing of ADFs. The application of the HME technique in the development of ADFs may overcome the challenges of opioid analgesic formulation development and provide improved protection against misuse and abuse, while also ensuring access to safe and effective use in patients with chronic pain. This review deals with a brief overview of strategies, with emphasis on HME to deter opioid abuse, in vitro characterization methods, commonly used excipients in the development of ADFs, and regulatory standards to meet the requirements of ADFs.

Aim: This study aimed to explore an affordable technique for the fabrication of Chitosan Nanoshuttles (CSNS) at the ultrafine nanoscale less than 100 nm with improved physicochemical properties, and cytotoxicity on the MCF-7 cell line. Background: Despite several studies reported that the antitumor effect of CS and CSNS could achieve intracellular compartment target ability, no enough information is available about this issue and further studies are required to address this assumption. Objectives: The objective of the current study was to investigate the potential processing variables for the production of ultrafine CSNS (less than; 100 nm) using Box-Behnken Design factorial design (BBD). This was achieved through a study of the effects of processing factors, such as CS concentration, CS/TPP ratio, and pH of the CS solution, on PS, PDI, and ZP. Moreover, the obtained CSNS was evaluated for physicochemical characteristics, morphology. In addition, hemocompatibility and cytotoxicity using Red Blood Cells (RBCs) and MCF-7 cell lines were investigated. Methods: Box-Behnken Design factorial design (BBD) was used in the analysis of different selected variables. The effects of CS concentration, sodium tripolyphosphate (TPP) ratio, and pH on particle size, Polydispersity Index (PDI), and Zeta Potential (ZP) were measured. Subsequently, the prepared CS nanoshuttles were exposed to stability studies, physicochemical characterization, hemocompatibility, and cytotoxicity using red blood cells and MCF-7 cell lines as surrogate models for in vivo study. Result: The present results revealed that the optimized CSNS has ultrafine nanosize, (78.3 ± 0.22 nm), homogenous with PDI (0.131 ± 0.11), and ZP (31.9 ± 0.25 mV). Moreover, CSNS has a spherical shape, amorphous in structure, and physically stable. Moreover, CSNS has biological safety as indicated by a gentle effect on red blood cell hemolysis, besides, the obtained nanoshuttles decrease MCF-7 viability. Conclusion: The present findings concluded that the developed ultrafine CSNS has unique properties with enhanced cytotoxicity, thus promising for use in intracellular organelles drug delivery.

Aim: Polyamidoamine (PAMAM) dendrimers are attracting interest of the scientists as vehicles for nucleic acid delivery due to their suitable properties. The highly positive surface charged of PAMAM enables an adequate interaction with negatively charged microRNAs. Purpose: The purpose of this study is to investigate the anti-tumor effect of microRNA Mimic let-7b loaded in PAMAM dendrimers (G5) on Non-Small Cell Lung Cancer (NSCLC) cells. Objective: In order to increase the anti-tumor effect, chloroquine is employed to enhance the endosomal escape which is counted as a limitation in the advancement of gene delivery. Nanoparticles (NPs) were coated with natural polysaccharide "Hyaluronic Acid (HA)" to develop biodegradable carriers with targeting moiety for over-expressed CD44 receptors on NSCLC cells. The size and zeta potential measurements, gel retardation, cellular uptake, cell viability and gene expression studies were investigated for the designed delivery system. Results: DLS analysis showed monodispersed small nanoparticles, which was in agreement with TEM results. Remarkably, NPs in the cells pretreated with chloroquine exhibited the highest cytotoxicity and were capable of inducing apoptosis. In cellular uptake study, NPs labeled with Fluorescein Isothiocyanate (FITC), were successfully taken up in cancer cells. Moreover, the expression study of three genes linked with cancer initiation and development in NSCLC, including KRAS, p-21, and BCL-2 indicated a decrease in KRAS and BCL-2 (oncogenic and anti-apoptotic genes) and increase in p-21 (apoptotic gene). Conclusion: All factors considered, the results declare that application of let-7b-loaded PAMAM-HA NPs in combination with chloroquine can be a promising therapeutic option in cancer cells inhibition. This fact has frequently been highlighted by many researchers upon the potentials of micro RNA delivery in cancer cells.

Purpose: The sole purpose of this study is to improve the solubility and dissolution of telmisartan by cocrystallization technique and apply a computational simulation approach to assess the nature of chemical interactions between telmisartan and coformer as well as the solvent contribution to the molecules for furnishing cocrystallization. Methods: The effects of various concentrations of coformer i.e. oxalic acid on physicochemical parameters and drug release were investigated. Results: Solubility studies suggested that cocrystallization technique with oxalic acid helps to increase the solubility of pure telmisartan of about 7 folds and drug release study revealed that telmisartan-oxalic acid cocrystals showed greater dissolution as compared to pure telmisartan. SEM study suggested that prepared telmisartan cocrystals showed rhomboid-shaped crystals with sharp edges and smooth surface. FTIR study revealed that shifting in the vibrational frequencies of C=O group of telmisartan in telmisartan- oxalic acid cocrystal indicates the formation of supra molecular hetero synthon of the cocrystal. DSC and XRD studies confirmed the formation of telmisartan-oxalic acid cocrystals. Computational simulation approach revealed that telmisartan and oxalic acid can interact with each other in the presence of methanol and water where oxalic acid can form interactions principally with the others. The interactions, thereof, may form several associations or bondings in between the drug and carrier modifying the planarity, bond energy, bond angles of both which subsequently lead to cocrystallization. Conclusion: So, the present research concluded that prepared telmisartan-oxalic acid cocrystal is a successful application of crystal engineering approach to improve the physicochemical properties as well as to enhance the solubility and dissolution of telmisartan.

Objective: The objective of this study was to evaluate the suitability of a ternary mixture of smart polymers comprised of Eudragit^®E100, Eudragit^®L100, and sodium alginate to serve as a carrier for sustained drug release for weakly basic drugs. The model drug chosen in this part of the study is Metronidazole. Methods: Matrix tablet formulations were prepared by either direct compression or by wet granulation. Dissolution studies were conducted using USP XXΠ rotating paddle apparatus in three different consecutive stages (pH 1.2, 4.8, and 6.8). Tablets made of low to intermediate proportions of sodium alginate and approximately equal proportions of Eudragit^®E100 and Eudragit^®L100 were found to have a significant modification of drug release rates. Results: Thus, indicating a potential for controlling the drug release for 12 hours depending on polymers ratios in the formulation. The ratio of sodium alginate to total Eudragit^® polymers and the ratio of Eudragit^®E100 to Eudragit^®L100 within the ternary polymeric composition were found critical in determining the controlled release performance. Conclusion: Results of swelling studies were in agreement with the dissolution behaviors of the tablets. The findings suggest the significance of the ternary polymeric compositions in controlling the release of a weakly basic drug, Metronidazole.

Purpose: The purpose of this research work was to evaluate the Pharmacokinetic (PK), Pharmacodynamic (PD), and the distribution pattern of mucoadhesive microspheres of nifedipine. Methods: Firstly, the emulsion solvent evaporation technique was used to prepare the mucoadhesive microspheres. The microspheres were characterized by Fourier Transform Infrared Spectroscopy (FTIR) and in vivo studies were carried on Wistar rats. Results: Blood samples of rats were withdrawal at 2, 4, and 8 h time interval, after the administration of Mucoadhesive microspheres of nifedipine (Mm-N) and the Saline solution of nifedipine (Ss-N) separately. The Area Under the Curve (AUC) of Mm-N was seven foaled and Cmax around four foaled high when compared with Ss-N with a significant difference P<0.005. Hypertension induced with DOCA (deoxycorticosterone acetate) and the Blood Pressure (BP) of hypertensive rats were recorded at 0, 0.5, 1, 2, 3, 4, 5, 6 h time interval after given Mm-N and Ss-N to different groups. The BP of rats was better control with Mm-N and regular after 2 h with high significant difference P<0.0001 however, the Ss-N have an insignificant difference with P>0.05. The Mm-N was distributed in the upper part of the Gastrointestinal Tract (GIT) after 8 h confirmed with the help of the fluorescence microscopic examination. Conclusion: This study indicates that the nifedipine was present in the blood for a more extended period, and the blood pressure was easily controlled with mucoadhesive microspheres of nifedipine. Therefore, mucoadhesive microspheres of nifedipine would be an excellent alternative over conventional drug delivery for the treatment of hypertension.

Objective: Periodontitis is an oral disease categorized by disturbance of periodontal tissue and the creation of periodontal pockets. Thymol (TH) loaded microsponge in situ gelling systems was formulated for local action in the periodontal cavity for the management of periodontitis. Methods: Solvent evaporation technique was utilized for the preparation of microsponges. A Fractional Factorial Design (FFD) was used to screen the high risk variables impacting the characteristics of the (TH) microsponges and further optimized using Box-Behnken design. The optimized microsponges were then characterized by DSC, SEM, antimicrobial activity, in-vitro release, and then incorporated in the in situ gelling system. A ligature model was used to induce periodontitis in Sprague Dawley rats. Results: The microsponges showed good characteristics, such as particle size, entrapment efficiency, and mucoadhesiveness of 45 μm, 92.99 ± 0.2%, 96 ± 0.26%, respectively. SEM revealed the spherical morphology of the microsponges with sustained release of TH for 10h and antimicrobial activity against S. mutans and C. albicans. Treatment with Thymol Loaded in situ Gel (THLMG) showed a decrease in gingival inflammation and tooth mobility as well as in serum biochemical parameters like serum Creactive proteins, leucocyte count, alkaline phosphatase, and tartrate-resistant acid phosphatase, when compared to disease group. The histopathological study of the periodontium confirmed a significant reduction of inflammation and alveolar bone destruction (p<0.05) in rats. Conclusion: THLMG decreased the infiltration of inflammatory cells and prevented osteoclastogenesis and osteoblast apoptosis, which further favored a decrease in inflammation and alveolar bone loss in periodontitis. Thus, THLMG could be a better alternative to synthetic antimicrobials and antibiotics to treat periodontitis.

Aim: Current work focuses on the improvement of the solubility and dissolution of ACF by the cocrystal approach. Background: Aceclofenac (ACF) is one of the commonly used Nonsteroidal Anti-Inflammatory Drug (NSAID) representing a variety of therapeutic applications including management of pain, inflammation, rheumatoid arthritis, and osteoarthritis, etc. But very low solubility and dissolution rate of ACF compromise its therapeutic utility. Now a day’s cocrystallization technique has emerged as a novel technique for modulation of the said problems. Objective: The Specific objectives of this research work were mechanochemical synthesis, characterization, and performance evaluation of aceclofenac cocrystal. Methods: ACF was screened with various pharmaceutically acceptable coformers (Selected from GRAS and EAFUS list) using MOPAC software and physical screening method to find out novel cocrystals of ACF with enhanced solubility and dissolution rate. Novel cocrystals (multi-component crystalline solid) of ACF with l-cystine were prepared by a neat grinding method and by liquid assisted grinding method. The synthesized cocrystals (ACF-l-CYS NG and ACF-l-CYS LAG) were characterized carefully by Differential Scanning Calorimetry (DSC), Infrared Spectroscopy (IR), and Powder XRay Diffraction (PXRD) to verify the formation of the cocrystals. Pharmaceutically significant properties such as powder dissolution rate, solubility, and stability of the prepared cocrystals were evaluated. Results: Compared to pure ACF, the prepared cocrystals showed superior solubility and dissolution rate. The prepared cocrystals were found to be stable and non-hygroscopic under study conditions. Conclusion: The cocrystallization technique was successfully utilized to increase the solubility and dissolution rate of aceclofenac.