Fabrication and Characterization of Pectin Films Containing Solid Lipid Nanoparticles for Buccal Delivery of Fluconazole.

Fluconazole (FZ) is a potential antifungal compound for treating superficial and systemic candidiasis. However, the use of conventional oral drug products has some limitations. The development of buccal film may be a potential alternative to oral formulations for FZ delivery. The present study involved the development of novel FZ-loaded solid lipid nanoparticles (FZ-SLNs) in pectin solutions and the investigation of their particle characteristics. The particle sizes of the obtained FZ-SLNs were in the nanoscale range. To produce pectin films with FZ-SLNs, four formulations were selected based on the small particle size of FZ-SLNs and their suitable polydispersity index. The mean particle sizes of all chosen FZ-SLNs formulations did not exceed 131.7 nm, and the mean polydispersity index of each formulation was less than 0.5. The properties of films containing FZ-SLNs were then assessed. The preparation of all FZ-SLN-loaded pectin films provided the mucoadhesive matrices. The evaluation of mechanical properties unveiled the influence of particle size variation in FZ-SLNs on the integrity of the film. The Fourier-transform infrared spectra indicated that hydrogen bonds could potentially form between the pectin-based matrix and the constituents of FZ-SLNs. The differential scanning calorimetry thermogram of each pectin film with FZ-SLNs revealed that the formulation was thermally stable and behaved in a solid state at 37 °C. According to a drug release study, a sustained drug release pattern with a burst in the initial stage for all films may be advantageous for reducing the lag period of drug release. All prepared films with FZ-SLNs provided a sustained release of FZ over 6 h. The films containing FZ-SLNs with a small particle size provided good permeability across the porcine mucosa. All film samples demonstrated antifungal properties. These results suggest the potential utility of pectin films incorporating FZ-SLNs for buccal administration.

Thermosensitive Poloxamer 407/Poly(Acrylic Acid) Hydrogels with Potential Application as Injectable Drug Delivery System.

Thermosensitive hydrogels are of great interest for in situ gelling drug delivery. The thermosensitive vehicle with a gelation temperature in a range of 30-36°C would be convenient to be injected as liquid and transform into gel after injection. To prepare novel hydrogels gelling near body temperature, the gelation temperature of poloxamer 407 (PX) were tailored by mixing PX with poly(acrylic acid) (PAA). The gelation behaviors of PX/PAA systems as well as the interaction mechanism were investigated by tube inversion, viscoelastic, shear viscosity, DSC, SEM, and FTIR studies. The gelation temperature of the plain PX solutions at high concentration of 18, 20, and 22% (w/w) gelled at temperature below 28°C, which is out of the suitable temperature range. Mixing PX with PAA to obtain 18 and 20% (w/w) PX with 1% (w/w) PAA increased the gelation temperature to the desired temperature range of 30-36°C. The intermolecular entanglements and hydrogen bonds between PX and PAA may be responsible for the modulation of the gelation features of PX. The mixtures behaved low viscosity liquid at room temperature with shear thinning behavior enabling their injectability and rapidly gelled at body temperature. The gel strength increased, while the pore size decreased with increasing PX concentration. Metronidazole, an antibiotic used for periodontitis, was incorporated into the matrices, and the drug did not hinder their gelling ability. The gels showed the sustained drug release characteristic. The thermosensitive PX/PAA hydrogel could be a promising injectable in situ gelling system for periodontal drug delivery.

Microphase Separation and Gelation of Methylcellulose in the Presence of Gallic Acid and NaCl as an In Situ Gel-Forming Drug Delivery System.

Novel hydrogels of methylcellulose (MC) with gallic acid (GA) and NaCl were developed for an in situ gel-forming delivery system. Plain MC and GA/NaCl/MC were characterized using micro-differential scanning calorimetry (micro-DSC), rheological and turbidity methods. The gelation temperatures of MC were reduced to body temperature with adding GA/NaCl. GA and NaCl caused slightly different effects on the gelation/degelation temperatures during heating/cooling, respectively, based on the different sensitivities of these three techniques. The gelation mechanism was investigated by UV spectrophotometry, and the hydrophobic interaction between the aromatic ring of GA and MC was verified. The NaCl/MC hydrogel had smaller micropores than GA/MC and MC, indicating a greater cross-linked density. Doxycycline (DX) was loaded into the systems and demonstrated a synergistic effect of DX/GA. Both GA and DX exhibited a sustained release. The hydrogel of GA/4NaCl/MC could be potentially used for the in situ delivery of DX for deep wound healing.

Characterization of freeze-dried gallic acid/xyloglucan.

BACKGROUND: Tamarind seed xyloglucan (TSX) is generally used for drug delivery systems. Gallic acid (GA) possesses various pharmacological activities. It has a good solubility and bioavailability but short half-life. PURPOSE: To prepare a sustained-release of GA to overcome its relatively short half-life. GA was blended with TSX and freeze-dried. The physicochemical properties of freeze-dried GA and freeze-dried GA/TSX were characterized, and the release profiles of GA from these freeze-dried samples were investigated. METHOD: All freeze-dried samples were characterized by PXRD, spectroscopic and thermal analyses. The dissolution studies were performed according to the United States Pharmacopeia (USP) XXX. RESULTS: According to FTIR, FT-Raman and (13)C CP/MAS NMR, the spectra of freeze-dried GA were similar to that of the anhydrous form. Nevertheless, DRIFTS and DSC were able to differentiate these two forms. The crystallinity of GA in the freeze-dried GA/TSX was the same as that of the freeze-dried GA. DSC indicates that there were interactions between GA and TSX. It was of interest that a freeze-dried sample with low amount of GA, 0.2% GA/1% TSX was mostly in an amorphous form. Moreover, all freeze-dried GA/TSX preparations demonstrated a sustained-release of GA compared to GA alone. The freeze-dried 1% GA/1% TSX provided the best sustained-release of GA of up to 240 min. CONCLUSIONS: TSX could change a crystal form of a small molecule to a mostly amorphous form. It was of importance that the freeze-dried GA/TSX could effectively retard the release of GA. These samples may be able to overcome the limitation for the therapeutic use of GA due to its short biological half-life.

Effect of Cremophor RH40, Hydroxypropyl Methylcellulose, and Mixing Speed on Physicochemical Properties of Films Containing Nanostructured Lipid Carriers Loaded with Furosemide Using the Box-Behnken Design.

This study aimed to examine the characteristics of H-K4M hydroxypropyl methylcellulose (HPMC) films containing nanostructured lipid carriers (NLCs) loaded with furosemide. A hot homogenization technique and an ultrasonic probe were used to prepare and reduce the size of the NLCs. Films were made using the casting technique. This study used a Box-Behnken design to evaluate the influence of three key independent variables, specifically H-K4M concentration (X1), surfactant Cremophor RH40 concentration (X2), and mixing speed (X3), on the physicochemical properties of furosemide-loaded NLCs and films. The furosemide-loaded NLCs had a particle size ranging from 54.67 to 99.13 nm, and a polydispersity index (PDI) ranging from 0.246 to 0.670. All formulations exhibited a negative zeta potential, ranging from -7.05 to -5.61 mV. The prepared films had thicknesses and weights ranging from 0.1240 to 0.2034 mm and 0.0283 to 0.0450 g, respectively. The drug content was over 85%. Film surface wettability was assessed based on the contact angle, ranging from 32.27 to 68.94°. Film tensile strength varied from 1.38 to 7.77 MPa, and their elongation at break varied from 124.19 to 170.72%. The ATR-FTIR analysis confirmed the complete incorporation of the drug in the film matrix. Therefore, the appropriate selection of values for key parameters in the synthesis of HPMC films containing drug-loaded NLCs is important in the effective development of films for medical applications.

Role of Bovine Serum Albumin Addition in Micellization and Gel Formation of Poloxamer 407.

The combination of the thermoresponsive polymer and protein has demonstrated great promise in its applications in drug delivery and tissue engineering fields. This study described the impact of bovine serum albumin (BSA) on the micellization and sol-gel transition behaviors of poloxamer 407 (PX). The micellization of aqueous PX solutions with and without BSA was examined using isothermal titration calorimetry. In the calorimetric titration curves, the pre-micellar region, the transition concentration region, and the post-micellar region were observed. The presence of BSA had no noticeable impact on critical micellization concentration, but the inclusion of BSA caused the pre-micellar region to expand. In addition to studying the self-organization of PX at a particular temperature, the temperature-induced micellization and gelation of PX were also explored using differential scanning calorimetry and rheology. The incorporation of BSA had no discernible effect on critical micellization temperature (CMT), but it did affect gelation temperature (Tgel) and gel integrity of PX-based systems. The response surface approach illustrated the linear relation between the compositions and the CMT. The major factor affecting the CMT of the mixtures was the concentration of PX. The alteration of the Tgel and the gel integrity were discovered to be a consequence of the intricate interaction between PX and BSA. BSA mitigated the inter-micellar entanglements. Hence, the addition of BSA demonstrated a modulating influence on Tgel and a softening effect on gel integrity. Understanding the influence of serum albumin on the self-assembly and gelation of PX will enable the creation of thermoresponsive drug delivery and tissue engineering systems with controlled gelation temperatures and gel strength.

Curcumin-loaded methacrylate pullulan with grafted carboxymethyl-ß-cyclodextrin to form hydrogels for wound healing: In vitro evaluation.

A pullulan (Pul)-derivative hydrogel was developed by introducing methacrylate (MA) groups and ß-cyclodextrin (ßCD) to form a Pul-ßCD-MA hydrogel by UV cross-linking. The MA was expected to improve the hydrogel's mechanical properties and the ßCD to increase the solubility of curcumin. Pul-ßCD-MA was successfully synthesized, as confirmed by the 1H NMR and FTIR spectra. Hydrogels were formed at Pul-ßCD-MA concentrations of 5 %, 7.5 %, or 10 % w/v. Pul-ßCD-MA showed enhanced curcumin solubility compared to Pul or Pul-MA. The morphological analysis of the hydrogel showed a porous structure. The concentration of ßCD affected the hydrogels' mechanical properties, and the 7.5 % hydrogel (with or without curcumin) did not fracture. The cumulative release of curcumin in the 7.5 % Pul-ßCD-MA hydrogel was 60 % over 8 h. The release profile fit the Korsmeyer-Peppas model. In vitro cytotoxicity tests revealed that hydrogels were biocompatible with human primary dermal fibroblast cells. Curcumin-loaded Pul-ßCD-MA hydrogels significantly accelerated wound healing compared to Pul-ßCD-MA hydrogels without curcumin loading. Therefore, the Pul derivative's hydrogel may be a promising material for wound healing.

Drug-Polymers Composite Matrix Tablets: Effect of Hydroxypropyl Methylcellulose (HPMC) K-Series on Porosity, Compatibility, and Release Behavior of the Tablet Containing a BCS Class I Drug.

The purpose of this research was to see how the physicochemical properties and porosity of matrix tablets containing various types of hydroxypropyl methylcellulose (HPMC) K series affected the release of propranolol hydrochloride (PNL). PNL is a class I drug (high solubility and permeability) according to the Biopharmaceutics Classification System (BCS), making it an excellent model drug used for studying extended-release drug products. The direct compression method was used to prepare the HPMC-based matrix tablets. PNL and the excipients were found to be compatible using Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). The surfaces of all the compressed HPMC-based matrix tablets were rough, with accumulated particles and small holes. The compressed HPMC-based matrix tablet porosity was also determined by using mercury porosimetry. The compressed HPMC-based matrix tablets made of low viscosity HPMC had tiny pores (diameter < 0.01 µm). The shorter polymeric chains are more prone to deformation, resulting in a small pore proportion. The compressed HPMC-based matrix tablets sustained the release of PNL for over 12 h. The release exponent values (n), which reflect the release mechanism of the drug from the tablets, ranged from 0.476 to 0.497. These values indicated that the release was governed by anomalous transport. The compressed HPMC-based matrix tablets have the potential for a sustained release of PNL.

Design and development of 3D-printed bento box model for controlled drug release of propranolol HCl following pharmacopeia dissolution guidelines.

The goal of this study was to develop a 3D-printed bento box model (3D-printed BB) with one or two chambers containing propranolol hydrochloride (PNL) as powder and matrix tablet for controlled drug release at varying times using United States Pharmacopeia (USP) dissolution guidelines. The 3D-printed BBs were made with commercial polyvinyl alcohol filament and a fused deposition modeling (FDM) 3D printer, with varying infill percentages and wall thicknesses. The physicochemical properties of the 3D-printed BBs, including appearance, thickness, size, weight, hardness, swelling, and erosion properties were investigated. The surface and cross-section morphologies of the 3D-printed BBs were characterized using a FESEM. According to FESEM images, the different infill percentages had a significant effect on the internal structure of the 3D-printed BBs' caps, but a minor effect on the internal structure of their walls. PNL release from the 3D-printed BB began in a pH 1.2 medium, followed by drug release in a pH 6.8 medium. Some formulations of 3D-printed BB could achieve a drug release percentage within all the ranges specified by USP dissolution guidelines. 3D-printed BBs, therefore, have the potential to revolutionize the future of the pharmaceutical industry by facilitating control of the amount of drugs released at predetermined intervals.

Thermosensitive Polymer Blend Composed of Poloxamer 407, Poloxamer 188 and Polycarbophil for the Use as Mucoadhesive In Situ Gel.

Herein, thermosensitive blends of poloxamer 407 (P407)/poloxamer 188 (P188)/polycarbophil (PCB) were developed in terms of maximized content of PCB (a mucoadhesive polymer) and desired temperature-dependent rheological properties of the blends as in situ gelling matrices. Maximizing PCB content while achieving the preferable rheological characteristics was accomplished through the Box-Behnken design. The quantitative effect of the polymer composition in the blends on the thermosensitive characteristics was evaluated using the fitted design model and the corresponding surface plots. The optimized P407/P188/PCB blend (OPT) was the mixture of 20.000, 7.349 and 0.595% (w/w) of P407, P188, and PCB, respectively. The thermosensitive micellization of OPT was investigated using differential scanning calorimetry which revealed an overlapping double endothermic peak caused by the temperature-induced micellization of pure micelles in co-existence with the micelles with attached PCB. Mixing PCB with the P407/P188 matrix promoted a more intense mucoadhesion of the blend. After incorporating metronidazole, a model hydrophilic drug, into OPT, the temperature-dependent characteristics of the hydrogel did not change. Metronidazole release from OPT was sustained by an anomalous mechanism. This optimal ternary hydrogel benefiting from thermosensitive gelling and mucoadhesive matrix might be used as a viable platform for mucoadhesive in situ gelling drug delivery.

3,4,5-Trihy-droxy-benzoic acid.

In the title compound, C(7)H(6)O(5), the three hy-droxy groups on the ring are oriented in the same direction. There are two intra-molecular O-H⋯O hydrogen bonds in the ring. In the crystal, there are several inter-molecular O-H⋯O hydrogen bonds and a short contact of 2.7150 (18) Šbetween the O atoms of the para-OH groups of adjacent mol-ecules.

Exploring potential coformers for oxyresveratrol using principal component analysis.

Oxyresveratrol (OXY) exhibits poor bioavailability due to its low solubility. Cocrystals are effective in improving solubility of OXY. In this study, principal component analysis (PCA) was employed for coformer selection using 5 variables (solubility parameter, logP, hydrogen bonding acceptor, hydrogen bonding donor and molecular volume). According to PCA analyses, nicotinamide (NCT) and proline (PRO) were grouped as the potential coformers. OXY-PRO and OXY-NCT cocrystals were obtained using a liquid assisted grinding method. The thermal and diffraction characteristics of both cocrystals were different from their starting materials. Based on FTIR and Raman spectroscopy, both interactions between the amide group of NCT and the phenolic hydroxyl groups of OXY, as well as π-π interactions between the aromatic rings of OXY and the pyridine ring of NCT were involved in the cocrystal formation. For OXY-PRO cocrystal, the carboxylate group of PRO interacted with the hydroxyl groups of OXY, OXY-NCT and OXY-PRO cocrystals enhanced the solubility and dissolution of OXY. Accordingly, PCA proved to be an effective technique in screening potential coformers for OXY and probably for other compounds. The improved solubility and dissolution of OXY in the form of cocrystal may provide a benefit for the use of OXY for pharmaceutical applications.

Characterization of supramolecular gels based on ß-cyclodextrin and polyethyleneglycol and their potential use for topical drug delivery.

Novel gels were prepared by blending ß-cyclodextrin and polyethyleneglycol (PEG) in the presence of K2CO3. The objective of this study was thus to characterize the gels using rheology, modulated temperature differential scanning calorimetry (MTDSC), turbidity measurements, and hot stage microscopy, and then investigate the potential use of the gel for topical drug delivery. Two types of supramolecular gels, GelL and GelH were prepared at a low temperature (below 50 °C) and at a high temperature (above 70 °C), respectively. Both gels were thermo-reversible. Upon heating, GelL could turn to GelH. Nevertheless, upon cooling, GelH that was more stable than GelL precipitated and GelL could not be reformed. GelL may form through simple complexation of polyethyleneglycol (PEG) with ß-cyclodextrin in the presence of K2CO3. However, GelH may form a specific complex or a pseudopolyrotaxane gel. For pharmaceutical application, GelL was investigated instead of GelH because the forming temperature of this gel was close to the human body temperature. The interactions among diclofenac sodium (DS), a model drug, and the components of the gel were examined using FTIR. These interactions may include ionic attraction and hydrogen bonds between the carboxylate groups of DS and the hydroxyl groups of PEG or ß-cyclodextrin and probably also the inclusion of the aromatic ring of DS into the cavity of ß-cyclodextrin. Furthermore, the release and permeation of diclofenac from GelL were significantly greater than those from a commercial gel. Therefore, GelL may be useful for the topical delivery of drugs.

Experimental FTIR and theoretical studies of gallic acid-acetonitrile clusters.

Gallic acid (3,4,5-trihydroxybenzoic acid, GA) has many possible conformers depending on the orientations of its three OH and COOH groups. The biological activity of polyphenolic compounds has been demonstrated to depend on their conformational characteristics. Therefore, experimental FTIR and theoretical studies of the GA-solvent clusters were performed to investigate the possible most favored conformation of GA. Acetonitrile (ACN) was selected as the solvent since its spectrum did not interfere with the OH stretching bands of GA. Also of importance was that these OH groups, in addition to the carboxyl group, of the GA are the most likely groups to interact with receptors. The solution of GA in the ACN solution was measured and the complex OH bands were deconvoluted to four component bands. These component bands corresponded to the three OH bands on the benzene ring and a broad band which is a combination band of mainly the OH of the COOH group and the inter- and intramolecular H-bonds from the OH groups on the ring. The conformations, relative stabilities and vibrational analysis of the GA monomers and the GA-ACN clusters were investigated using the B3LYP/6-311++G(2d,2p) method. Conformational analysis of the GA monomer yielded four most possible conformers, GA-I, GA-II, GA-III and GA-IV. These conformers were subsequently used for the study of the GA:ACN clusters at the 1:1, 1:2 and 1:4 mole ratios. The IR spectra of the most stable structures of these clusters were simulated and the vibrational wavenumbers of the OH and C=O groups were compared with those from the experiment. The FTIR component bands were comparable to the computed OH bands of the GA-I-(ACN)(2), GA-IV-(ACN)(2) and GA-I-(ACN)(4) clusters. Furthermore, the C=O stretching bands and the bands in the regions of 1800-1000 cm(-1) obtained by computing and the experiment were similar for these clusters. Thus, GA-I and GA-IV are the most preferable conformations of GA in ACN and perhaps in the polar environment around the receptor sites of GA.

SAXS and ATR-FTIR studies on EBT-TSX mixtures in their sol-gel phases.

Our previous study demonstrated that mixtures of tamarind seed xyloglucan (TSX) with appropriate concentrations of eriochrome black T (EBT) produced a gel that could be of benefit for medical use. Here, the sol-gel systems of various fresh and aged mixtures were further investigated using rheological measurements. The nanostructural changes of EBT-TSX sol-gel phases were analyzed using SAXS. The interactions between EBT and TSX in the sol and gel states were examined using ATR-FTIR. SAXS data analysis demonstrated that the mixture containing lower concentration of EBT formed rod-like structures and that with higher concentrations of EBT produced flat particles. The sizes of the TSX structures from the aged mixtures in the gel stage were larger than those from the same mixtures in the sol state. ATR-FTIR spectral changes revealed that the azo and sulfonic acid groups of EBT interacted with the TSX, and the characteristic spectrum of the sulfonic acid group of EBT could discriminate between the sol and gel state of the EBT-TSX systems. The interactions between EBT and TSX may cause conformational changes to TSX and facilitate the sol-gel transition or formation of a gel.

Effect of Eriochrome Black T on the gelatinization of xyloglucan investigated using rheological measurement and release behavior of Eriochrome Black T from xyloglucan gel matrices.

A novel gel system was obtained by mixing aqueous solutions of tamarind seed xyloglucan (TSX) and Eriochrome Black T (EBT), an antiangiogenic compound. The shear-viscosity flow curves revealed that all the studies mixtures displayed a shear thinning behavior. Viscosity increased with increasing EBT concentrations. According to frequency sweep tests, mixtures at EBT concentration of 1.30% and 2.50% (w/v) in 1% (w/v) TSX formed a weak gel. The time sweep tests revealed that these mixtures remained as sol at room temperature (25 degrees C) for a long period of time but turned into gel in a short time at body temperature (37 degrees C). The in vitro EBT release profiles demonstrated sustained release of EBT. Loading concentration of EBT affected the gel strength and consequently the release mechanism of EBT. According to release kinetic analyses, the release profiles of 1.30% and 2.50% (w/v) EBT systems occur through an anomalous mechanism and Fickian diffusion, respectively. In conclusion, these EBT-TSX systems appear to be suitable as injectable implants for sustained delivery of EBT at a site of application, and as such they may be beneficial for the future treatment of solid malignant tumors.