Current Drug Delivery - Volume 18, Issue 8, 2021

The cell's power house, mitochondrion, is a vital organelle for drug targeting in the treatment of many diseases due to its fundamental duties and function related to cell proliferation and death. The mitochondrial membrane comprises bilayer artifact and poses extremely negative potential, creating hurdles for therapeutic molecules in reaching mitochondria. To accomplish mitochondrial targeting, the scientific community has explored diverse pharmaceutical formulations like liposomes, polymeric nanoparticles (NPs), and inorganic NPs. However, the game changing technology was a modification of these carriers by mitochondriotropic moiety, dequalinium chloride (DQA) or delivering the chemotherapeutics by DQAsomes. The DQA represents a distinctive mitochondriotropic delocalized cation that displays their selectivity towards accumulation in mitochondria of carcinoma cells. Attributed to this characteristics, DQAsomes have been formulated using DQA and explored for successful mitochondrial targeting of bioactives. In this review, it is discussed the effectiveness of DQA nanocarriers which efficiently and selectively transmit the cytotoxic drug to the tumor cell. The DQA based nanoformulations have evidently displayed augmented pharmacological and therapeutic outcomes than their counterparts both in vitro and in vivo. Thus, DQAsomes symbolizes an ideal carrier with excellent potential as mitochondrial targeting agent.

Chronic wounds remain a significant public problem and the development of wound treatments has been a research focus for the past few decades. Despite advances in the products derived from endogenous substances involved in a wound healing process (e.g., growth factors, stem cells, and extracellular matrix), effective and safe wound therapeutics are still limited. There is an unmet need to develop new therapeutics. Various new pathways and targets have been identified and could become a molecular target in designing novel wound agents. Importantly, many existing drugs that target these newly identified pathways could be repositioned for wound therapy, which will facilitate fast translation of research findings to clinical applications. This review discusses the newly identified pathways/targets and their potential uses in the development of wound therapeutics. Some herbs and amphibian skins have been traditionally used for wound repairs and their active ingredients have been found to act in these new pathways. Hence, screening these natural products for novel wound therapeutics remains a viable approach. The outcomes of wound care using natural wound therapeutics could be improved if we can better understand their cellular and molecular mechanisms and fabricate them in appropriate formulations, such as using novel wound dressings and nano-engineered materials. Therefore, we also provide an update on the advances in wound therapeutics from natural sources. Overall, this review offers new insights into novel wound therapeutics.

The polyelectrolyte complexes (PECs) are adaptable constructs shaped by electrostatic interaction between biopolymers with inverse charges. Polyelectrolyte edifices comprise an exceptional class of polymeric mixtures comprising of polyions with inverse charges, which can be charged either cationically or anionically. Significant advancement has been made in the course of recent years towards new medication conveyance frameworks. The subject of broad, essential and applied exploration covers the marvel of interpolymer collaborations and polyelectrolyte complex development. Basically, applied polyelectrolytes raise on the grounds that the advantages of supportability are perceived in the scholarly world and modern examination settings. Polyelectrolytes are a form of polymer that has endless ionizable practical arrangements. Ionized polyelectrolytes in the arrangement can form a complex with an oppositely charged particle called a polyelectrolyte complex. The review article emphasizes on PECs and their classification, characterization, as well as a critical analysis of the current research and applicability in the drug delivery technology.

Cardiovascular diseases cover various disorders like ischemic heart disease, hyperlipidemia, atherosclerosis, myocardial infarction, hypertension, etc. There are many synthetic drugs available for the treatment of cardiovascular therapy. However, they have several drawbacks like high dosing, toxicity, elevated blood potassium levels, low blood pressure, gastrointestinal issues, etc. To overcome these side effects of synthetic drugs, targeting the drug to the specific cardiac tissue is the best novel method in cardiovascular therapy. The highest targeting efficacy of ligand- based therapy with proper mechanisms and improved expandability provides a novel therapeutic strategy in cardiovascular diseases. Ligand therapy is more cost-effective compared to cell- based therapy. The surface area of protein is much larger than the orally bioavailable drug. Therefore, the targeting of various less active drug molecules to the particular ligand can be possible. The efficacy of ligands to induce cardiomyocytes proliferation has been ratified. The fact that ligand- based approaches are effective for cardiac transformation has been pointed out. Ligands interact with proteins in target cells, which are influenced by chemical signals. These various receptors selectively bind to biased ligands and energize the intracellular signaling pathway. The ligands can directly stabilize the active receptor conformations by a non-standard connective site. The key function of ligands is functional selectivity, which enhances the therapeutic efficacy and minimizes the side effects of drugs through the interpretation of signal transduction pathways. This review covers the role and effectiveness of novel ligands in cardiovascular disorders.

Nowadays, cancer is one of the deadliest diseases affecting an annually enormous number of people. Around 9.6 million people had died from different cancer types in 2018. Chemotherapy is considered to be a mainline treatment, and systemic administration of a single anticancer agent is also considered a vital clinical debacle of chemotherapy in cancer management. The formulators have been focusing currently onto procuring maximum benefit with the lowest aftereffects and maximum safety and efficacy for the patients undergoing chemotherapy. This review offers a perspective on the future developments of encapsulating food bioactive compounds with anticancer agents in a multifunctional single nanoliposomal delivery system. In the last decade, the paradigm shift was seen in formulating drug delivery systems for cancer treatment. Currently, food bioactive compounds are being taken as a hot subject by researchers, especially for the treatment of cancer owing to both preventative and curative quality. This review collects the utilization of liposomes in the delivery of anticancer drugs by encapsulating with food bioactive compounds by the oral administration. The authors coined the name of this combination is “Combisomes” as a fourth generation liposomes. Authors opine that “Combisomes” can tackle cancer minimizing side effects encountered from the usual anticancer agents. “Combisomes” will purvey a safe platform for the delivery of food bioactive compounds and anticancer agents for managing cancer with better safety prospects.

Background: D-Amino acid oxidase (DAO) is an H2O2-generating enzyme, and tumor growth suppression by selective delivery of porcine DAO in tumors via the cytotoxic action of H2O2 has been reported. DAO isolated from Fusariumspp. (fDAO) shows much higher enzyme activity than porcine DAO, although the application of fDAO for antitumor treatment has not yet been determined. Objective: The purpose of this study was to prepare enzymatically highly active pegylated-fDAO, and to determine whether it accumulates in tumors and exerts a potent antitumor effect in tumor- bearing mice. Methods: Polyethylene glycol (PEG; Mw. 2000) was conjugated to fDAO to form PEGylated fDAO (PEG-fDAO). PEG-fDAO was intravenously administered into S180 tumor-bearing mice, and the body distribution and antitumor activity of PEG-fDAO was determined. Results: The enzyme activity of PEG-fDAO was 26.1 U/mg, which was comparable to that of fDAO. Intravenously administered PEG-fDAO accumulated in tumors with less distribution in normal tissue except in the plasma. Enzyme activity in the tumor was 60-120 mU/g-tissue over 7-20 h after i.v. injection of 0.1 mg of PEG-fDAO. To generate the H2O2 in the tumor tissue, PEG-fDAO was intravenously administered, and then, D-phenylalanine was intraperitoneally administered after a lag time. No remarkable tumor suppression effect was observed under conditions used in this study, compared to the non-treated group. Conclusion: The results suggest that PEG-fDAO maintained high enzymatic activity after pegylation. Treatment with PEG-fDAO conferred high enzyme activity on tumor tissue; 3-6 fold higher than that of previously reported pDAO; however, high enzyme activity in the plasma limited repeated treatment owing to lethal toxicity, which seemingly led to poor therapeutic outcome. Overall, the use of PEG-fDAO is promising for antitumor therapy, although the suppression of DAO activity in the plasma would also be required rather than only the increase in DAO activity in the tumor for an antitumor effect.

Background: pH sensitive dendrimers attached to nanocarriers, as one of the drug release systems, have become quite popular due to their ease of manufacture in experimental conditions and the ability to generate fast drug release in the targeted area. This kind of fast release behavior cannot be represented properly in most of the existing kinetic mathematical models. Besides, these models have either no pH dependence or pH dependence added separately. Therefore, they remained one dimensional. Objective: The aim of this study was to establish the proper analytic equation to describe the fast release of drugs from pH sensitive nanocarrier systems, and to combine it with the pH dependent equation for to establish a two-dimensional model for whole system. Methods: We used four common kinetic models for the comparison and we fitted them to the release data. As a result, only Higuchi and Korsmeyer-Peppas models show acceptable suitable results. None of these models have pH dependence. To get a better description for pH triggered fast release, we observed the behavior of the slope angle of the release curve. Then we proposed a new analytic equation by using relation between the slope angle and time. Result: By adding a pH dependent equation, we assumed the drug release is “on” or “off” above/below specific pH value and we modified a step function to get a desired behavior. Conclusion: Our new analytic model shows good fitting, not only one-dimensional time dependent release, but also two-dimensional pH dependent release, that provides a useful analytic model to represent release profiles of pH sensitive fast drug release systems.

Background: Metformin Hydrochloride (MH) is an oral anti-hyperglycemic agent belonging to the biguanide class of drugs. Objective: The present study involves the formulation and evaluation of gastro-retentive floating microparticles containing MH as a model drug for the prolongation of absorption time. Methods: Three levels of a three-factor, Box-Behnken design were used to evaluate the critical formulation variables. Microparticles were prepared using a water-in-oil-in-water double-emulsion solvent evaporation method and examined in terms of production yield, particle size, entrapment efficiency, floating ability, morphology, FTIR (Fourier transform infrared spectroscopy), and in vitro drug release. Results: The optimum conditions for preparing MH microparticles were predicted to be the content of ethyl cellulose content (150 mg),poly (-caprolactone) (150 mg), and polyvinyl alcohol (1%w/v).The optimized MH microparticles were found to be spherical with a mean size of 350.2 μm. Entrapment efficiency was 58.62% for microparticles. 63.94% of microparticles showed floating properties. The FTIR analysis confirmed no chemical linkage between microparticle components. in vitro release study showed a controlled release for up to 8h. Conclusion: These results demonstrated that MH microparticles, as a drug delivery system, may be useful to achieve a controlled drug release profile suitable for oral administration and may help to reduce the dose of the drug and to improve patient compliance.

Aim: In this study, a novel D-α-tocopheryl polyethylene glycol succinate (TPGS) modified bovine serum albumin (BSA) nanoparticles (NPs) were developed for delivery of Anastrozole (ANZ) which is optimized by Box-Behnken design (BBD). Fabricated TPGS-ANZ-BSA NPs were evaluated for their physicochemical and drug release characteristics. Methods: TPGS-ANZ-BSA NPs were prepared by desolvation thermal gelation method and the effects of critical process parameter (CPP) which are BSA amount, TPGS concentration and stirring speed on the critical quality attributes (CQA) such as % drug loading (%DL) and particle size were studied using BBD. TPGS-ANZ-BSA NPs were characterized using different spectroscopic techniques including UV-Visible and FTIR is used to confirm the entrapment of ANZ in BSA. DSC and PXRD revealed the amorphization of ANZ in the TPGS-ANZ-BSA NPs after freeze drying. Scanning electron microscopy (SEM) analysis was performed for the surface morphology analyses NPs. In vitro release studies were performed at pH 5.5 and pH 7.4 for 48h to mimic tumour microenvironment. Results: The BBD optimized TPGS-ANZ-BSA NPs showed 107 nm particle size with %DL 8.5± 0.5%. The spectroscopic and thermal characterizations revealed the successful encapsulation of ANZ inside the NPs. The TPGS-ANZ-BSA NPs were found to exhibit burst release at pH 5.5 and sustained release at pH 7.4. The short-term stability displayed no significant changes in physical properties TPGS-ANZ-BSA NPs at room temperature for a period one month. Conclusion: The BBD optimized TPGS-ANZ-BSA nanoparticles showed enhanced physiochemical properties for ANZ and potential candidates for anticancer agent drugs delivery.

Aim: Present investigation was aimed to fabricate nanocrystal of exemestane, an anticancer drug with poor dissolution properties and oral bioavailability. Methods: Influence of various process parameters on the formulation of exemestane nanosuspension using media milling technique were investigated in the trial batches. Box-Behnken design was applied with independent variables identified in the preliminary studies, viz. X1-Milling time, X2-Amount of stabilizer and X3-Amount of milling agent. In vitro dissolution and in vivo studies were carried out. Solid state characterization (PXRD, SEM, and DSC) studies demonstrated physical changes in drug due to nano-crystallization. Accelerated stability studies of optimized formulation were carried out. Results: Individual process attributes exhibited a significant effect on the average particle size of exemestane nanosuspension. Dissolution studies revealed enhancement in drug release rate as compared to pure exemestane powder. The in vivo pharmacokinetic parameters of exemestane nanosuspension showed significant improvement in Cmax and AUC0-t, about 283.85% and 271.63%, respectively suggesting amelioration in oral bioavailability by 2.7-fold as compared to pure exemestane. Accelerated stability studies of the optimized formulation suggested stability of the nanocrystals for at least a six-month period. Conclusion: Nanocrystals prepared by media milling technique were successful in improving the poor dissolution properties and oral bioavailability of exemestane.

Background: Prussian Blue (PB) is available as conventional release dosage form “Radiogardase” with effective daily dose of 3-10 g (very high). The target site is the duodenum, where it inhibits the enterohepatic circulation of Cs & Tl ions, enhancing their fecal excretion. Objective: To enhance efficacy, target release, reduce the dose and side effects, oral pH-dependent matrix formulation of PB based on in-situ gelation of sodium alginate along with calcium salts was formulated and evaluated. Methods: Different combinations of matrix granules were formulated and optimized. The optimized one was compressed using Polyvinylpyrrolidone K30 (Pvp K30) in different batches and optimized. Langmuir adsorption isotherm was used to assess in-vitro binding efficacy of formulation to thallium using atomic absorption spectroscopy. The proof of concept i.e., drug release in the duodenum was studied through pharmacoscintigraphy using radiolabeled formulation in rabbits. Results: The optimized granules showed no drug release in an acidic medium for 2 h whereas complete empty of the basket in a basic medium within 30-60 minutes. The matrix tablet formulation with Pvp K30 (10% w/w) was optimized with desired hardness and optimum in-vitro release profile. The release data fitted to various linear kinetic models, Hixson-Crowell r² (0.9906) best fit, confirmed the erosion-based release mechanism. The maximum binding capacity (MBC) was found significantly higher (89.60 mg Tl/g formulation) than that of PB API (65.90 mg Tl /g PB API). Pharmacoscintigraphic images confirmed intact formulation in the stomach up to 2h and burst release in intestine thereafter. Conclusion: The results exemplify oral pH-dependent PB matrix formulation which achieved desirable target release at the duodenum and in-vitro binding efficacy towards Tl ion was appreciable.

Aim: Present research work focuses on the improvement of biopharmaceutical properties of aceclofenac (ACF) by the cocrystal approach. Background: ACF is one of the frequently used Nonsteroidal Anti-Inflammatory Drugs (NSAID). ACF is a BCS Class - II drug (low solubility and high permeability) with poor solubility and low oral bioavailability. Hence, the improvement in solubility and bioavailability of ACF is very crucial for successful product development. Nowadays, pharmaceutical cocrystals are considered a novel solid form of drugs. These cocrystals may have different physicochemical as well as biopharmaceutical properties as compared to the parent drug. In a previous study, the cocrystal of ACF (ACF-l-CYS NG and ACF-UREA NG) was successfully prepared and characterized. These cocrystals have shown superior solubility and dissolution rate than pure ACF in HCl buffer (pH 1.2). The synthesized cocrystals were also found non-hygroscopic and stable for 6 months under standard test settings. However, pharmacokinetic evaluation of these cocrystals has not been explored yet. Objective: The specific objective of this research work was the measurement of bioavailability and other pharmacokinetic parameters of ACF cocrystals prepared by the mechanochemical grinding method. Methods: Cocrystals of ACF with l-cystine and urea were prepared by neat grinding (NG) method and in-vivo oral bioavailability of prepared cocrystals was measured in Wistar rats. The plasma drug concentration was measured by high-performance liquid chromatography (HPLC), and the pharmacokinetic data was analyzed by “PK solver” software. Results: Percent relative bioavailability of ACF-l-CYS NG and ACF-UREA NG cocrystals in Wistar rats was found to be 242.05 ± 65.27and 178.93 ± 45.21 respectively, which were significantly higher (ANOVA, P < 0.05) than that of pure ACF. Conclusion: The present study indicates that the enhanced aqueous solubility of the prepared cocrystals leads to enhanced oral bioavailability of ACF. Thus, the cocrystals may be an alternative crystalline form of the drug that can enhance the solubility, dissolution rate, and oral bioavailability of many poorly soluble drugs.

Aim: This research work aimed to target the early morning peak symptoms of chronic stable angina through formulating antianginal drug, Trimetazidine (TMZ) in a pulsatile-release tablet. Methods: The core formulae were optimized using 22.31 factorial design to minimize disintegration time (DT) and maximize drug release after 5 minutes (Q5min). Different ratios of Eudragit S100 and Eudragit L100 were used as a coating mixture for the selected core with or without a second coating layer of hydroxypropyl methylcellulose (HPMC E50). The different formulation variables were statistically optimized for their effect on lag time and drug release after 7 hours (Q7h) using Box- Behnken design. The optimized formula (PO) was subjected to stability study and pharmacokinetic assessment on New Zealand rabbits. Results: The optimal core (F8) was found to have 1.76 min disintegration time and 61.45% Q5min PO showed a lag time of 6.17 h with 94.80% Q7h and retained good stability over three months. The pharmacokinetics study confirmed the pulsatile–release pattern with Cmax of 206.19 ng/ml at 5.33 h (Tmax) and 95.85% relative bioavailability compared to TMZ solution. Conclusion: Overall pulsatile-release tablets of TMZ successfully released the drug after a desirable lag time, providing a promising approach for early morning anginal symptoms relief.

Background: Combination of different chemotherapy drugs and nanoparticles as a carrier has shown promising delivery system in cancer treatment. Doxorubicin is considered a potent anticancer drug. However, its off-target activities and possible side effects make its use limited. Recently, in the field of nanomedicine, different nanoconjugates have been developed as a unique platform for the delivery of therapeutic drugs. Aims: The aim of the present study is to evaluate the best possible combination for efficient delivery of DOX with combination of gold, silver and zinc oxide nanoparticles to target site against carbon tetrachloride induced rat hepatotoxicity. Methods: Effect of different conjugates administrated for 14 consecutive days was evaluated. Results: In comparison to DOX, Au:DOX, ZnoO:DOX and Ag:DOX showed less sign of liver fibrosis as evaluated by serum enzymes and histopathological analysis. However, among all the conjugates, Ag: DOX conjugate showed the most significant results. The serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase values were (111.2 ± 38.21, 323.2 ± 46.88 and 303.6 ± 73.80 respectively) very close to control group (72.2 ± 19.41, 368 ± 59.78 and 259.4 ± 61.54 respectively). Conclusion: Our results demonstrated that Ag: DOX may exhibit hepato-protective activity against CCl4 induced liver damage.