Development and Optimization of Andrographis paniculata Extract-Loaded Self-Microemulsifying Drug Delivery System Using Experimental Design Model.

The objectives of this study were to develop an optimized formulation for an Andrographis paniculata extract (AGPE)-loaded self-microemulsifying drug delivery system (SMEDDS) using an experimental design and evaluate the characteristics of the developed SMEDDS. The solubility of andrographolide (AGP) in various solvents was investigated. The pseudo-ternary phase was constructed to provide an optimal range for each component to form microemulsions (MEs). The formulation was optimized using an I-optimal design mixture type, where the physical stability, droplet size, polydispersity index, and zeta potential were examined. Soft capsules of the optimized AGPE-loaded SMEDDS were manufactured. The dissolution and ex vivo membrane permeation were studied. Oleic acid, Tween® 80, and PEG 400 were the best solubilizers for AGP. The promising surfactant to co-surfactant ratio to generate ME was 3:1. The optimized SMEDDS contained 68.998% Tween® 80, with 13.257% oleic acid and 17.745% PEG 400. The assayed content of AGP, uniformity of dosage unit, and stability complied with the expected specifications. The dissolution and membrane permeability of AGPE-loaded SMEDDS was significantly improved from the A. paniculata extract (p < 0.05). All in all, the developed optimized AGPE-loaded SMEDDS was proven to contain optimal composition and AGP content where a stable ME could spontaneously be formed with enhanced delivery efficacy.

Antibody-decorated chitosan-iodoacetamide-coated nanocarriers for the potential delivery of doxorubicin to breast cancer cells.

Using an active targeting approach of chemotherapeutics-loaded nanocarriers (NCs) with monoclonal antibodies is a potential strategy to improve the specificity of the delivery systems and reduce adverse reactions of chemotherapeutic drugs. Specific targeting of the human epidermal growth factor receptor-2 (HER-2), expressed excessively in HER-2-positive breast cancer cells, can be achieved by conjugating NCs with an anti-HER-2 monoclonal antibody. We constructed trastuzumab-conjugated chitosan iodoacetamide-coated NCs containing doxorubicin (Tras-Dox-CHI-IA-NCs) as a tumor-targeted drug delivery system, during the study. Chitosan-iodoacetamide (CHI-IA) was synthesized and utilized to prepare trastuzumab-conjugated NCs (Tras-NCs). The morphology, physicochemical properties, drug loading, drug release, and biological activities of the NCs were elucidated. The Tras-NCs were spherical, with a particle size of approximately 76 nm, and had a positive zeta potential; after incorporating the drug, the size of the Tras-NC increased. A prolonged, 24-h drug release from the NCs was achieved. The Tras-NCs exhibited high cellular accumulation and significantly higher antitumor activity against HER-2-positive breast cancer cells than the unconjugated NCs and the drug solution. Therefore, Tras-Dox-CHI-IA-NCs could be a promising nanocarrier for HER-2-positive breast cancer.

Chitosan capped-gold nanoparticles as skin penetration enhancer for small molecules: A study in porcine skin.

Skin is considered one of the most convenient sites for drug administration. The present study evaluated the effect of gold nanoparticles stabilized by chitosan (CS-AuNPs) and citrate ions (Ci-AuNPs) on skin permeation of sodium fluorescein (NaFI) and rhodamine b base (RhB) as small model hydrophilic and lipophilic permeants, respectively. CS-AuNPs and Ci-AuNPs were characterized by transmitted electron microscopy (TEM) and dynamic light scattering (DLS). Skin permeation was investigated using porcine skin with diffusion cells and confocal laser scanning microscopy (CLSM). The CS-AuNPs and Ci-AuNPs were spherical-shaped nanosized particles (38.4 ± 0.7 and 32.2 ± 0.7 nm, respectively). The zeta potential of CS-AuNPs was positive (+30.7 ± 1.2 mV) whereas that of Ci-AuNPs was negative (-60.2 ± 0.4 mV). The skin permeation study revealed that CS-AuNPs could enhance the permeation of NaFI with enhancement ratio (ER) of 38.2 ± 7.5, and the effect was superior to that of Ci-AuNPs. CLSM visualization suggested that skin permeation was enhanced by improving the delivery through the transepidermal pathway. However, the permeability of RhB, a lipophilic molecule, was not significantly affected by CS-AuNPs and Ci-AuNPs. Moreover, CS-AuNPs had no cytotoxic toward human skin fibroblast cells. Therefore, CS-AuNPs are a promising skin permeation enhancer of small polar compounds.

Mussel-inspired poly(hydroxyethyl acrylate-co-itaconic acid)-catechol/hyaluronic acid drug-in-adhesive patches for transdermal delivery of ketoprofen.

This research aimed to create new hydrophilic drug-in-adhesive patches for transdermal drug delivery. Poly(hydroxyethyl acrylate-co-itaconic acid)-catechol (PHI-cat) and hyaluronic acid (HA) were used as main components in the pressure-sensitive adhesive. Citric acid and aluminium hydroxide were exploited as crosslinking agents and ketoprofen was employed as a model delivering compound. The adhesive performance, physicochemical properties, drug-polymer interaction, drug crystallization, drug content, drug permeation through the skin, and coordination polymer network of the patches were investigated. In addition, skin irritation and adhesion potential in human subjects were assessed. Due to the ability of catechol groups to form interaction with the skin tissue, the patches containing PHI-cat and HA offered a considerably greater adhesion ability to human skin compared with the patches without catechol and commercial patches. Furthermore, the patches had good physical and chemical stability. Therefore, these catechol-functionalized patches may be potential transdermal drug delivery systems with excellent adhesive properties for the delivery of a drug through the skin.

Bioinspired ketoprofen-incorporated polyvinylpyrrolidone/polyallylamine/ polydopamine hydrophilic pressure-sensitive adhesives patches with improved adhesive performance for transdermal drug delivery.

Inspired by the natural mussel adhesive mechanism, three different materials-polydopamine (PDA), polyvinylpyrrolidone (PVP), and polyallylamine (PAM)-were used to make innovative pressure-sensitive adhesives (PSAs) for transdermal delivery of ketoprofen. PDA was synthesized under alkaline conditions using a self-polymerization reaction and was exploited as a cross-linking agent due to its biocompatibility. The adhesive performance, physicochemical properties, drug content, and drug permeation through the skin were examined. Moreover, in vivo skin irritation and skin adhesion performance were investigated. PVP/PAM/PDA PSAs showed a significantly higher adhesion to human skin compared with commercial patches owing to the interaction between the catechol groups presented on the patches and the skin. In addition, the patches were stable for six months. Consequently, the PVP/PAM/PDA patches exhibited outstanding tissue adhesiveness, enabling universal tissue adherence while causing no skin tissue irritation or inflammatory reaction.

The utilization of mangosteen pericarp extract for anticoccidial drug replacement in broiler feed.

The use of anticoccidial drugs in broilers has led to concerns, especially the drug residues in meat and the occurrence of drug resistance. This study aimed to extract, standardize, quantify and utilize mangosteen pericarp extract (MPE) containing α-mangostin as a replacement for anticoccidial drugs in broiler feed. The pericarp was acquired from different areas of Thailand and used for extraction and standardization. The antioxidant activity of the extract was evaluated. The extract was formulated into granules, and the flowability and stability of the granules were assessed. The MPE formulation was added to the broiler feed and then fed to the broilers that were infected with Eimeria tenella. The growth rate and intestinal lesion score (post-mortem) of the broilers were assessed. The pericarp obtained passed the identification test and phytochemical analyses. The active compound, α-mangostin, was best extracted using 95% ethanol. The MPE had superior antioxidant activity compared to standard antioxidants. Granules of the extract formulated with Avicel® PH102 provided desirable flowability and stability. The broilers fed with the feed containing 500 mg/kg α-mangostin showed a similar growth rate and post-mortem lesion score compared with the control group and those that received feed containing 60 mg/kg salinomycin. Our findings demonstrated that MPE with a high content of the active compound could be developed and used in place of anticoccidial drugs in the broiler feed.

Maleimide-functionalized carboxymethyl cellulose: A novel mucoadhesive polymer for transmucosal drug delivery.

The objective of this research was to develop a novel mucoadhesive polymer for drug delivery applications based on N-(2-aminoethyl) maleimide-functionalized carboxymethyl cellulose in which the weight ratios of the materials were tuned to explore the condition providing the highest maleimide content on the polymer. The polymers were synthesized from N-(2-aminoethyl) maleimide that was conjugated to carboxymethyl cellulose with their mucoadhesive properties examined by tensile testing, rheology, and flow-through analysis and their biocompatibilities evaluated on the human gingival fibroblast cell line (HGF-1). The anti-inflammatory drug benzydamine was loaded into mucoadhesive-polymer-based tablets and used to demonstrate the application of the synthesized polymer. The polymer exhibited superior mucoadhesive capability compared to carboxymethyl cellulose through the interaction between maleimide moiety and mucin. The functionalized polymer also possessed the ability to control the release of benzydamine with Higuchi's release model and was proven to be a potential candidate in mucoadhesive drug delivery.

Nanostructured lipid carrier-embedded polyacrylic acid transdermal patches for improved transdermal delivery of capsaicin.

Capsaicin has been used as a topical treatment for skeletomuscular and neuropathic pain. However, it has some side effects when it is applied to the skin such as burning, erythema, and skin irritation resulting in poor patient compliance. These adverse effects are caused by the rapid penetration of capsaicin into the outer layer of the epidermis and low permeation to the dermis layer. This study aimed to develop nanostructured lipid carriers (NLCs) embedded transdermal patches for improved transdermal delivery of capsaicin. An optimum formulation of NLCs (0.3% capsaicin) with a particulate size smaller than 200 nm, narrow size distribution, and acceptable colloidal stability was used for preparing transdermal patches. Polyacrylic acid (7%) was employed as the polymer base of the transdermal patches as it provided high adhesive performance and a sustained release of capsaicin. Moreover, the patches containing capsaicin-loaded NLCs could offer a higher deposition of capsaicin in the deeper layer of the skin compared to the conventional capsaicin patches. In vivo skin irritation studies indicated that the conventional capsaicin patches can cause skin irritation and redness, whereas capsaicin NLCs-loaded patches exhibited lower skin side effects. Therefore, the capsaicin NLCs-loaded patches could be a potential delivery system of capsaicin through the skin with possibly reduced skin irritation.

Synthesis of Polyethylene Glycol Diacrylate/Acrylic Acid Nanoparticles as Nanocarriers for the Controlled Delivery of Doxorubicin to Colorectal Cancer Cells.

Doxorubicin (Dox) is known for its potential to deliver desirable anticancer effects against various types of cancer including colorectal cancer. However, the adverse effects are serious. This study aimed to synthesize polyethylene glycol diacrylate (PEGDA)/acrylic acid (AA)-based nanoparticles (PEGDA/AA NPs) for Dox delivery to colorectal cancer cells. The NPs were synthesized using free-radical polymerization reaction using the monomers PEGDA and AA with their physical properties, drug loading and release, biocompatibility, and anticancer effect evaluated. The NPs were spherical with a size of around 230 nm, with a 48% Dox loading efficiency and with loading capacity of 150 µg/mg. Intriguingly, the NPs had the ability to prolong the release of Dox in vitro over 24 h and were non-toxic to intestinal epithelial cells. Dox-loaded PEGDA/AA NPs (Dox-NPs) were able to effectively kill the colorectal cancer cell line (HT-29) with the Dox-NPs accumulating inside the cell and killing the cell through the apoptosis pathway. Overall, the synthesized PEGDA/AA NPs exhibit considerable potential as a drug delivery carrier for colon cancer-directed, staged-release therapy.

Development and Evaluation of Novel Water-Based Drug-in-Adhesive Patches for the Transdermal Delivery of Ketoprofen.

The objective of this study was to develop novel water-based drug-in-adhesive pressure-sensitive adhesives (PSAs) patches for the transdermal delivery of ketoprofen, employing poly(N-vinylpyrrolidone-co-acrylic acid) copolymer (PVPAA) and poly(methyl vinyl ether-alt-maleic anhydride) (PMVEMA) as the main components. The polymers were crosslinked with tartaric acid and dihydroxyaluminium aminoacetate using various polymer ratios. Ketoprofen was incorporated into the PVPAA/PMVEMA PSAs during the patch preparation. The physicochemical properties, adhesive properties, drug content, release profile, and skin permeation of the patches were examined. Moreover, the in vivo skin irritation and skin adhesion performance in human volunteers were evaluated. The patches prepared at a weight ratio of PVPAA/PMVEMA of 1:1 presented the highest tacking strength, with desirable peeling characteristics. The ketoprofen-loaded PVPAA/PMVEMA patches exhibited superior adhesive properties, compared to the commercial patches, because the former showed an appropriate crosslinking and hydrating status with the aid of a metal coordination complex. Besides, the permeated flux of ketoprofen through the porcine skin of the ketoprofen-loaded PVPAA/PMVEMA patches (4.77 ± 1.00 µg/cm2/h) was comparable to that of the commercial patch (4.33 ± 0.80 µg/cm2/h). In human studies, the PVPAA/PMVEMA patches exhibited a better skin adhesion performance, compared with the commercial patches, without skin irritation. In addition, the patches were stable for 6 months. Therefore, these novel water-based PSAs may be a potential adhesive for preparing drug-in-adhesive patches.

Catechol-modified chitosan/hyaluronic acid nanoparticles as a new avenue for local delivery of doxorubicin to oral cancer cells.

Local administration of chemotherapeutic drugs to a tumor site in the oral cavity can provide high drug concentrations in the tumor area and reduce systemic side effects. In this work, catechol (Cat)-modified chitosan/hyaluronic acid (HA) nanoparticles (NPs), hereinafter referred to as Cat-NPs, were developed as a new carrier to deliver doxorubicin (DOX) to oral cancer cells. The Cat moiety of the NPs allowed the excellent adhesion of the carrier to the oral mucosa and sustained local delivery of DOX into the oral cavity. Cat-NPs were generated from Cat-functionalized succinyl chitosan and Cat-bearing HA via ionic gelation. Negatively charged and spherical Cat-NPs measuring approximately 160 nm in size were obtained. The modified NPs demonstrated superior mucoadhesive capability on ex vivo porcine oral mucosal tissues compared with the unmodified NPs. DOX could be loaded onto the modified NPs with a high loading capacity of 250 µg/mg, and sustained-release characteristics were observed. The DOX-loaded Cat-NPs (DOX-NPs) inhibited the growth of the HN22 oral squamous cell carcinoma cell line with a low IC50. Moreover, the DOX-NPs were taken up, accumulated, and induced apoptosis in cells more extensively compared with free DOX. These findings reflect the potential use of the synthesized Cat-NPs as a new carrier for the local delivery of DOX to oral cancer cells. Further in vivo studies should be carried out to confirm the clinical applications of these NPs.

Synthesis of novel N-vinylpyrrolidone/acrylic acid nanoparticles as drug delivery carriers of cisplatin to cancer cells.

This study aimed to synthesize novel polymeric nanoparticles (NPs) bound with cisplatin for the treatment of oral cancer. The NPs were synthesized from N-vinylpyrrolidone (NVP) and acrylic acid (AA) using 2 different methods based on a surfactant-free emulsion polymerization reaction. An azo initiator (V50) and bisacrylamide crosslinker were used in the reaction to create the NPs. The morphology, physicochemical characteristics, drug loading, and in vitro release were evaluated. Moreover, the cytotoxicity, death induction mechanism, and in vitro intracellular accumulation of cisplatin in HN22 cells were also investigated. Relatively spherical NPs with negative charge were obtained from both synthesis methods with the size in the range of 136-183 nm. The NPs were bound to cisplatin via coordination bond which was confirmed by FT-IR. The optimal NPs to cisplatin ratio was found to be 1:10 with %entrapment efficiency and loading capacity of 12-18% and 4 mmol/g, respectively. Approximately 47-83% of cisplatin was released from the NPs in 7 days in the presence of chloride ions depending on the pH of the release medium. The novel NPs from both methods were nontoxic to gingival fibroblast cells while the IC50 values of cisplatin-loaded NPs on HN22 cells were just above 20 µg/mL. In addition, the cisplatin-loaded NPs demonstrated a higher percentage in the early apoptotic death mechanism. Higher cellular deposition of cisplatin at the earlier period was obtained by the cisplatin-loaded NPs suggesting a slower but safer cancer-killing effect. Therefore, these novel NPs may be promising nanocarriers of cisplatin for oral cancer treatment.

Preactivated-thiolated polyacrylic acid/1-vinyl pyrrolidone nanoparticles as nicotine carriers for smoking cessation.

This study aimed to develop nicotine-loaded mucoadhesive preactivated-thiolated polymeric nanoparticles (PNPs) for smoking cessation. 2-Mercaptonicotinic acid (2MNA) was coupled as dithionicotinic acid dimer and used in the preactivation of thiolated polyacrylic acid/vinyl pyrrolidone PNPs (thiolated AA/VP PNPs). Preactivated-thiolated AA/VP PNPs were synthesized through surfactant-free emulsion polymerization and coupling reactions. The structural attributes of the preactivated-thiolated AA/VP PNPs were characterized using Fourier-transform infrared spectroscopy and proton nuclear magnetic resonance spectroscopy. The particle size and zeta potential were evaluated by dynamic light scattering evaluation. The morphology of the preactivated-thiolated AA/VP PNPs was examined using scanning electron microscopy. In addition, the mucoadhesive properties, drug loading and release, and biocompatibility of the preactivated-thiolated AA/VP PNPs were assessed. The spherical preactivated-thiolated AA/VP PNPs were successfully synthesized with a particle size of 410.3 ± 7.4 nm and a negative surface charge. The preactivated-thiolated AA/VP PNPs exhibited superior mucoadhesive properties compared with the thiolated AA/VP PNPs. Drug loading by PNP to a nicotine ratio of 1 : 1 provided desirable loading capacity and % loading efficiency of 285.7 ± 36.7 µg mg-1 and 57.1 ± 7.4%, respectively. More than 50% of the nicotine contained in the PNPs was rapidly released in the first hour, followed by a sustained release for up to 12 h. Moreover, the synthesized PNPs were non-toxic to human gingival cells. Therefore, the preactivated-thiolated AA/VP PNPs may be a candidate carrier of nicotine for smoking cessation.