Current Drug Delivery - Volume 19, Issue 3, 2022

Lichens are commonly used as essential traditional medicines to treat various conditions, including skin disorders, wounds, digestive, respiratory, obstetric, and gynecological problems in many cultures in Africa, Asia, Europe, Haitian, Oceania, and North and South America. Lichens have been deeply investigated for their phytochemical properties and, to date, numerous compounds (also known as substances) have been successfully isolated from the extracts. However, the low solubility and bioavailability of pure lichen substances have been widely recognized as significant issues hindering their biological applications. Recently, several groups have investigated the properties and the potential applications of lichen metabolites-based liposomal formulations and revealed a substantial improvement in their solubility, bioactivity, and toxicity in the animal. Thus, in this topical review, we aimed to provide an overview of liposomal structures, the efficacy of liposomal formulations, as well as their beneficial effects as compared to the free compounds themselves.

The COVID-19 pandemic has caused a significant burden on public health worldwide. Currently, there are limited medications for the treatment of COVID-19 in patients with Parkinson’s disorder (PD). Several antiviral drugs and other pharmacotherapies have shown promising results and are used by various delivery methods. Among the antiviral drugs, amantadine alone was reported to provide therapeutic benefit against COVID-19 in patients with PD. Here, we propose novel strategies for pulmonary drug delivery technology of antiviral drug, amantadine. As such pulmonary delivery of this drug or in combination with the additional antiviral drugs could be a more effective strategy for the treatment of COVID-19-related complications in patients with PD. Furthermore, the important benefits and limitations of this novel delivery technology will be discussed.

Natural cyclodextrins (CDs) are macrocyclic starch molecules discovered a decade ago, in which α-, β-, and γ-CD were commonly used. They originally acted as pharmaceutical excipients to enhance the aqueous solubility and alter the physicochemical properties of drugs that fall under class II and IV categories according to the Biopharmaceutics Classification System (BPS). The industrial significance of CDs became apparent during the 1970s as scientists started to discover more of CD’s potential in chemical modifications and the formation of inclusion complexes. CDs can help in masking and prolonging the half-life of drugs used in cancer. Multiple optimization techniques were discovered to prepare the derivatives of CDs and increase their complexation and drug delivery efficiency. In recent years, due to the advancement of nanotechnology in pharmaceutical sectors, there has been growing interest in CDs. This review mainly focuses on the formulation of cyclodextrin conjugated nanocarriers using graphenes, carbon nanotubes, nanosponges, hydrogels, dendrimers, and polymers to achieve drug-release characteristics specific to cells. These approaches benefit the discovery of novel anti-cancer treatments, solubilization of new drug compounds, and cell specific drug delivery properties. Due to these unique properties of CDs, they are essential in achieving and enhancing tumor-specific cancer treatment.

Cancer is the leading cause of death globally. There are several differences between cancer cells and normal cells. Of all the therapies, chemotherapy is the most prominent therapy to treat cancer. However, the conventional drug delivery system that is used to deliver poorly aqueous soluble chemotherapeutic agents has several obstacles such as whole-body distribution, rapid excretion, degradation before reaching the infected site, side effects, etc. Nanoformulation of these insoluble aqueous agents is the emerging delivery system for targeted and increasing solubility. Among all the three methods (physical, chemical and biological) chemical and biological methods are mostly used for the synthesis of Nanovehicles (NVs) of different sizes, shapes and dimensions. The passive targeting delivery system in which NVs supports the pharmacological agents (drugs/genes) is a good way for resolving the obstacles with a conventional delivery system. It enhances the therapeutic efficacy of pharmacological agents (drugs/genes). These NVs have several specific characters like small size, large surface area to volume ratio, surface functionalization, etc. However, this delivery is not able to deliver site-specific delivery of drugs. An active targeting delivery system in which pharmacological agents are loaded on NVs to attack directly on cancer cells and tissues is a superior way for delivering the pharmacological agents compared to the passive targeting delivery system. Various targeting ligands have been investigated and applied for targeting the delivery of drugs such as sugar, vitamin, antibodies, protein and peptides, etc. This targeted ligand’s support to guide the NVs, accumulated directly on the cancer cells with a higher level of cellular internalization compared to passive targeting and conventional delivery system.

Diabetes mellitus is found to be among the most suffered and lethal diseases for mankind. Diabetes mellitus type-1 is caused by the demolition of pancreatic islets responsible for the secretion of insulin. Insulin is the peptide hormone (anabolic) that regulates the metabolism of carbohydrates, fats, and proteins. Upon the breakdown of the natural process of metabolism, the condition leads to hyperglycemia (increased blood glucose levels). Hyperglycemia demands outsourcing of insulin. The subcutaneous route was found to be the most stable route of insulin administration but faces patient compliance problems. Oral Insulin delivery systems are the patient-centered and innovative novel drug delivery system, eliminating the pain caused by the subcutaneous route of administration. Insulin comes in contact across various barriers in the gastrointestinal tract, which has been discussed in detail in this review. The review describes about the different bioengineered formulations, including microcarriers, nanocarriers, Self-Microemulsifying Drug Delivery Systems (SMEDDs), Self-Nanoemulsifying drug delivery systems (SNEDDs), polymeric micelles, cochleates, etc. Surface modification of the carriers is also possible by developing ligand anchored bioconjugates. A study on evaluation has shown that the carrier systems facilitate drug encapsulation without tampering the properties of insulin. Carrier-mediated transport by the use of natural, semi-synthetic, and synthetic polymers have shown efficient results in drug delivery by protecting insulin from harmful environment. This makes the formulation readily acceptable for a variety of populations. The present review focuses on the properties, barriers present in the GI tract, overcome the barriers, strategies to formulate oral insulin formulation by enhancing the stability and bioavailability of insulin.

Background: The bitter taste and strong irritation of valnemulin hydrochloride limit its wide clinical application in pigs by oral. Method: In order to improve its palatability and residence time in the body, the valnemulin hydrochloride taste-masking granules with sustained-release were prepared by combining solid dispersion based on fatty acid with wet granulation. The formulation was screened by orthogonal test with content, yield, grain size and angle of repose as evaluation indexes. Result: The results showed that the optimal granules were composed of corn starch, sucrose, citric acid, valnemulin hydrochloride and myristic acid at a ratio of 40: 20: 20: 11: 19. The daily feed intake of pigs in the optimum taste-masking granule groups was similar to that of its self-control, and significantly higher than that in the valnemulin hydrochloride active ingredient group, suggesting that the optimum granules have satisfactory palatability. The prepared granules improved the oral bioavailability of valnemulin hydrochloride by 3.04 folds and extended its mean residence time (MRT) by 2.33 folds. Conclusion: The granules developed in this study could obviously improve the palatability and sustained release of valnemulin hydrochloride. The producing method of granules by combining solid dispersion powder with wet granulation can provide ideas for other drugs with poor palatability and a short half-life.

Background: Oxaprozin is labeled as a Class II drug in the biopharmaceutical classification system, and its poor solubility in the entire gastrointestinal tract may be the main reason for its insufficient oral absorption capacity. Objective: The purpose of this study was to develop an oxaprozin formulation to enhance its oral absorption. Methods: Oxaprozin-loaded microemulsions were prepared using the titration method and pseudoternary phase diagram. Characterization experiments were performed on microemulsion preparations, including pH, particle size, shape, zeta potential, and stability (thermodynamic, dilution, and differential scanning calorimetry). Then, the in vitro release of the microemulsion and in vivo pharmacokinetics in rats were evaluated. Results: Several microemulsion formulations were prepared. The optimal formulation was 15% oleoyl macrogolglycerides, 35% Tween 20/isopropanol (Km=2), and 50% distilled water. Its particle size met the requirements, and it had a spherical shape with a negatively charged surface. This microemulsion-loaded drug was applied to in vitro release and in vivo pharmacokinetic experiments at 7.47 mg/mL. In vitro release of the oxaprozin-loaded microemulsion best fit the firstorder model, while the microemulsion preparation had a certain sustained-release effect. In vivo pharmacokinetic experiments indicated that the microemulsion formulation significantly delayed the peak time of the blood concentration and simultaneously prolonged the half-life of drug elimination. Conclusion: The obtained data revealed satisfactory results for this novel microemulsion of oxaprozin, which is very meaningful for clinical trials.

Objective: Current in-situ injectable implants of buprenorphine (BP) such as Sublocade^® consist of N-methyl-2-pyrrolidone (NMP)-dissolved PLGA. To control the initial burst release of Sublocade^® during the first 24 hours after injection, we here used a BP in-situ forming composite (ISFC) employing different molecular weights of PLGA-PEG-PLGA triblock. Methods: The triblock was synthesized by Ring-Opening Polymerization (ROP) using PEG molecules with weights of 1500, 3000, and 4000 Da via the melting method. The specifications of the triblocks were evaluated by ¹H-NMR, FTIR, GPC, and DSC. The sol-gel, gel-precipitate temperatures, in-vitro release, and composites’ morphology, degradation, and toxicity were assessed for determining the features of ISFC 1500, ISFC 3000, and ISFC 4000 formulations. ROP was performed successfully via the melting method. The yields of all polymerization reactions were greater than 83.4%. Results: The PEG 1500 triblock showed both sol-gel and gel-precipitate temperatures, but PEG 3000 and 4000 only showed a sol-precipitate temperature. The values of initial burst release of BP from ISFC 1500, ISFC 3000, and ISFC 4000 were 6.52 ± 0.22%, 12.39 ± 0.61%, and 15.80 ± 0.98%, respectively. BP release from the ISFCs wascompleted over three weeks for ISFC 1500 and 10 days for ISFC 3000 and ISFC 4000. The composites containing PEG 3000 and PEG 4000 were more spongy and porous than PEG 1500. The ISFC 1500 delivered a higher cell viability (95.17 ± 1.15%) compared with ISFC 3000 (86.37 ± 2.25%) and ISFC 4000 (79.70 ± 3.77%). Conclusion: These results indicated that ISFC 1500 wasbiocompatible and delivered suitable early initial burst reactions compared with ISFC 3000 and 4000 and might be a good candidate for preparing sustained-release formulation of BP.

Background: Due to the increased resistance against existing antibiotics, research is essential to discover new and alternative ways to control infections induced by resistant pathogens. Objective: The goal of the current scrutinization was to enrich the dissolution rate and antibacterial property of cefixime (CEF) orally. Methods: To achieve the desired results, chitosan nanoparticles (NPs) containing CEF were fabricated using the ionic gelation method. Central Composite design has been applied to get the optimal formulation for the delivery of CEF. The effect of three variables, such as the concentration of chitosan, tripolyphosphate, and tween 80, on the characteristics of NPs was evaluated. Results: The optimized NPs involved a relatively monodispersed size distribution with an average diameter of 193 nm and a zeta potential of about 11 mV. The scanning tunneling microscope confirmed the size of NPs. The surface morphology of NPs was observed by scanning electron microscopy. The calorimetric analysis indicated the amorphous state of cefixime in the formulation. The dissolution rate of NPs in aqueous media was acceptable and the model of release kinetics for CEF from NPs followed the Peppas model. The potency of CEF in NPs against various types of bacteria was hopefully efficient. The ex-vivo release study demonstrated higher penetration of NPs from the rat intestine compared to free drug. The cell culture study showed the safety of the optimized formulation. Conclusion: Chitosan NPs could be considered a significant system for the controlled delivery of CEF due to its antibacterial effectiveness.

Background: The rutin loaded chitosan-alginate nanoparticles (RCANP) were prepared using an ion gelation method. The optimized RCANP4 formulation composed of rutin: alginate: chitosan with the ratio of 1.24:5:2. The particle size, zeta potential, and entrapment efficiency of RCANP4 formulation were found to be 168.4 ± 11.23 nm, -24.7 ± 1.5 mV, and 91.23 ± 1.1%, respectively. The in vitro drug release of RCANP4 formulation was found to be 88.89 ± 2.9% within 24 h. The Fourier transform infrared spectroscopy (FT-IR) of RCANP4 revealed all characteristic groups of rutin, confirming the successful loading of rutin into the nanoparticles. Methods: Due to rutin entrapment in the chitosan sodium alginate matrix, a broad curve was observed in the Differential Scanning Calorimetry (DSC) study of RCANP4. The RCANP4 was found to be uniform and spherical revealed from Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM). RCANP4 showed 3.54 times more bioavailability than free rutin, resulting in more internalization of rutin in systemic circulation. The results of plasma glucose levels of diabetic rats administered with RCANP4 and rutin were evident that RCANP4 showed effective antidiabetic activity compared to rutin. Results: The results obtained for glucose uptake in HepG2 cells, the RCANP4 caused a significant (P < 0.05) increase in glucose uptake in contrast to rutin. In vitro cytotoxicity results explained that RCANP4 could significantly (P < 0.05) reduce the cells viability rate compared with rutin. It may be due to the internalization of RCANP4 formulations in systemic circulation. Conclusion: The results also showed that RCANP4 could significantly reduce cell viability over 24 h and 48 h compared to free rutin.

Background: Cefpodoxime Proxetil (CPD) is a broad-spectrum cephalosporin indicated in respiratory and urinary tract infections. CPD is a BCS class IV drug with pH-dependent solubility and has poor bioavailability. This study investigated the challenges of developing ternary components based on solid SNEDDS of CPD for in vitro dissolution rate enhancement and self-solidifying behaviour. Methods: Tween 80, Transcutol and PEG6000 were employed as surfactants, solvents and solidifiers for a base of ternary components to develop self-solidifying solid SNEDDS, respectively. Ternary phase diagrams were used to characterize solidifying behaviour of ternary components in different proportions. S-SNEDDS formulations were drawn on the solidification areas available in the phase diagram and characterized for IR, XRD, DSC and in vitro drug release in various pH media. Results: Ternary components for the preparation of self-solidifying solid SNEDDS were selected based on drug solubility. FTIR and DSC characterization studies ruled out any drug interaction between CPD and components chosen to prepare S-SNEDDS. CPD was transformed from a crystalline into an amorphous state in ternary dispersions as revealed from XRD data. Optimized formulation (S-S 1) demonstrated more than 95% of drug release irrespective of the pH environments of the medium. Calculation of dissolution efficiency and similarity factors indicate that S SNEDDS resulted in a higher drug dissolution rate over binary dispersion (p<0.01). The stability studies showed that the S SNEDDS were stable in performances and CPD assay. Conclusion: The present investigation provides an alternative approach for enhancing the CPD dissolution rate using self-solidifying solid SNEDDS exhibited solidification behaviour at ambient temperature conditions and drug loading, which could be exploited over conventional dosage form.

Background: Flurbiprofen (FLBP), used in the treatment of ulcerative colitis, has a short biological half-life. Frequent intake of FLBP may lead to some serious gastric complications, which makes FLBP an ideal candidate for sustained release preparation to the Ileo-colonic region of the gastrointestinal tract (GIT). Objective: The objective of this study was to investigate the potential of Eudragit coated chitosan microspheres in delivering Flurbiprofen in a sustained manner to the Ileo-colonic region of the GIT for treatment of ulcerative colitis. Methods: In the present study, mucoadhesive chitosan microspheres were prepared using the emulsion solvent evaporation method by varying different process parameters. Optimized chitosan microspheres were coated with Eudragit L-100 and Eudragit S-100. A 32 full factorial design was applied for optimization. The effect of independent variables (Eudragit L-100 to Eudragit S-100 ratio and stirring speed) on dependent variable i.e. percentage cumulative drug release (%CDR) at 3 h and 24 h was evaluated. The optimized batch was evaluated by FT-IR, DSC study, XRD study and SEM analysis. Results: Discrete spherical shape chitosan microspheres with entrapment efficiency of up to 95.4% were obtained and selected for coating. Chitosan microspheres were coated successfully with different ratios of Eudragit L-100 to Eudragit S-100. The release profile of the optimized batch matches with the desired release profile. FLBP was found to be stable and molecularly dispersed in the polymer matrix. Conclusion: Taken together it can be concluded that prepared microspheres may be considered as a suitable for delivering FLBP to the Ileo-colonic region of the GIT in the treatment of ulcerative colitis.