Glycerol- and diglycerol-based polyesters: Evaluation of backbone alterations upon nano-formulation performance.

Despite the success of polyethylene glycol-based (PEGylated) polyesters in the drug delivery and biomedical fields, concerns have arisen regarding PEG's immunogenicity and limited biodegradability. In addition, inherent limitations, including limited chemical handles as well as highly hydrophobic nature, can restrict their effectiveness in physiological conditions of the polyester counterpart. To address these matters, an increasing amount of research has been focused towards identifying alternatives to PEG. One promising strategy involves the use of bio-derived polyols, such as glycerol. In particular, glycerol is a hydrophilic, non-toxic, untapped waste resource and as other polyols, can be incorporated into polyesters via enzymatic catalysis routes. In the present study, a systematic screening is conducted focusing on the incorporation of 1,6-hexanediol (Hex) (hydrophobic diol) into both poly(glycerol adipate) (PGA) and poly(diglycerol adipate) (PDGA) at different (di)glycerol:hex ratios (30:70; 50:50 and 70:30 mol/mol) and its effect on purification upon NPs formation. By varying the amphiphilicity of the backbone, we demonstrated that minor adjustments influence the NPs formation, NPs stability, drug encapsulation, and degradation of these polymers, despite the high chemical similarity. Moreover, the best performing materials have shown good biocompatibility in both in vitro and in vivo (whole organism) tests. As preliminary result, the sample containing diglycerol and Hex in a 70:30 ratio, named as PDGA-Hex 30%, has shown to be the most promising candidate in this small library analysed. It demonstrated comparable stability to the glycerol-based samples in various media but exhibited superior encapsulation efficiency of a model hydrophobic dye. This in-depth investigation provides new insights into the design and modification of biodegradable (di)glycerol-based polyesters, potentially paving the way for more effective and sustainable PEG-free drug delivery nano-systems in the pharmaceutical and biomedical fields.

Modification of Poly(Glycerol Adipate) with Tocopherol and Cholesterol Modulating Nanoparticle Self-Assemblies and Cellular Responses of Triple-Negative Breast Cancer Cells to SN-38 Delivery.

This study aimed to fabricate new variations of glycerol-based polyesters by grafting poly(glycerol adipate) (PGA) with hydrophobic bioactive moieties, tocopherol (TOC), and cholesterol (CHO). Their effects on nanoparticle (NP) formation, drug release, and cellular responses in cancer and normal cells were evaluated. CHO and TOC were successfully grafted onto PGA backbones with 30% and 50% mole grafting. Increasing the percentage of mole grafting in both molecules increased the glass transition temperature and water contact angle of the final polymers but decreased the critical micelle concentration of the formulated particles. PGA-TOC NPs reduced the proliferation of MDA-MB-231 cancer cells. However, they enhanced the proliferation of primary dermal fibroblasts within a specific concentration range. PGA-CHO NPs minimally affected the growth of cancer and normal cells. Both types of NPs did not affect apoptosis or the cell cycle of cancer cells. PGA-CHO and PGA-TOC NPs were able to entrap SN-38, a hydrophobic anticancer drug, with a particle size <200 nm. PGA-CHO NPs had a higher drug loading capacity and a greater drug release than PGA-TOC NPs. However, SN-38-loaded PGA-TOC NPs showed higher toxicity than SN-38 and SN-38-loaded PGA-CHO NPs due to the combined effects of antiproliferation and higher cellular uptake. Compared with SN-38, the drug-loaded NPs more profoundly induced sub-G1 in the cell cycle analysis and apoptosis of cancer cells in a similar pattern. Therefore, PGA-CHO and PGA-TOC polymers have potential applications as delivery systems for anticancer drugs.

CD44-Targeted Lipid Polymer Hybrid Nanoparticles Enhance Anti-Breast Cancer Effect of Cordyceps militaris Extracts.

This study aimed to improve the anticancer effect of Cordyceps militaris herbal extract (CME) on breast cancer cells with hyaluronic acid (HYA) surface-decorated lipid polymer hybrid nanoparticles (LPNPs) and evaluate the applicability of a synthesized poly(glycerol adipate) (PGA) polymer for LPNP preparation. Firstly, cholesterol- and vitamin E-grafted PGA polymers (PGA-CH and PGA-VE, respectively) were fabricated, with and without maleimide-ended polyethylene glycol. Subsequently, CME, which contained an active cordycepin equaling 9.89% of its weight, was encapsulated in the LPNPs. The results revealed that the synthesized polymers could be used to prepare CME-loaded LPNPs. The LPNP formulations containing Mal-PEG were decorated with cysteine-grafted HYA via thiol-maleimide reactions. The HYA-decorated PGA-based LPNPs substantially enhanced the anticancer effect of CME against MDA-MB-231 and MCF-7 breast cancer cells by enhancing cellular uptake through CD44 receptor-mediated endocytosis. This study demonstrated the successful targeted delivery of CME to the CD44 receptors of tumor cells by HYA-conjugated PGA-based LPNPs and the new application of synthesized PGA-CH- and PGA-VE-based polymers in LPNP preparation. The developed LPNPs showed promising potential for the targeted delivery of herbal extracts for cancer treatment and clear potential for translation in in vivo experiments.

Extemporaneous Preparation of 20 mg/mL Ganciclovir in Artificial Tears in Comparison with Sterile Water for Ophthalmic Administration: Formulation and Stability Study.

Ganciclovir is available as a lyophilized powder for reconstitution and is normally used to treat ophthalmic viral infections. The use of ganciclovir in artificial tears containing hydrocolloid polymers may prove beneficial to patients during drug application, by prolonging contact time and providing a moistening effect. Therefore, this study aimed to extemporaneously prepare 20 mg/mL ganciclovir in artificial tears and compare its stability with that of a similar concentration of ganciclovir in sterile water (SWI) for ophthalmic administration. First, a compatibility study of the drug with commercial artificial tears found that it was compatible with artificial tears containing sodium hyaluronate (HYA). Subsequently, ganciclovir/0.1% HYA (HYA0.1) and ganciclovir/SWI eyedrops (EDs) in low-density polyethylene (LDPE) eyedrop bottles packed in light-shielded zipper bags were evaluated for their stability at 5 ± 3 °C and 30 ± 2 °C. The results revealed that ganciclovir/SWI ED had good physicochemical and microbiological stability when stored at 5 ± 3 °C for 12 weeks and at 30 ± 2 °C for 8 weeks. Meanwhile, ganciclovir/HYA0.1 ED was stable for 8 weeks when kept at 5 ± 3 °C and at 30 ± 2 °C, but ganciclovir in 0.3% HYA ED could be stored at 5 ± 3 °C for 8 weeks. Nevertheless, particulate matter may need to be investigated using a suitable method to ensure the absence of invisible particles in these preparations. Of these results, ganciclovir/HYA artificial tears and SWI EDs show potential for use as home medications for the treatment of ophthalmic viral infections.

Ketorolac-Loaded PLGA-/PLA-Based Microparticles Stabilized by Hyaluronic Acid: Effects of Formulation Composition and Emulsification Technique on Particle Characteristics and Drug Release Behaviors.

This study aimed to develop ketorolac microparticles stabilized by hyaluronic acid based on poly(lactide-co-glycolide) (PLGA), poly(lactide) (PLA), and their blend for further application in osteoarthritis. The polymer blend may provide tailored drug release and improved physicochemical characteristics. The microparticles were prepared by water-in-oil-in-water (w/o/w) double emulsion solvent evaporation using two emulsification techniques, probe sonication (PS) and high-speed stirring (HSS), to obtain the microparticles in different size ranges. The results revealed that the polymer composition and emulsification technique influenced the ketorolac microparticle characteristics. The PS technique provided significantly at least 20 times smaller average size (1.3-2.2 µm) and broader size distribution (1.5-8.5) than HSS (45.5-67.4 µm and 1.0-1.4, respectively). The encapsulation efficiency was influenced by the polymer composition and the emulsification technique, especially in the PLA microparticles. The DSC and XRD results suggested that the drug was compatible with and molecularly dissolved in the polymer matrix. Furthermore, most of the drug molecules existed in an amorphous form, and some in any crystalline form. All of the microparticles had biphasic drug release composed of the burst release within the first 2 h and the sustained release over 35 days. The obtained microparticles showed promise for further use in the treatment of osteoarthritis.

Delivery of acetogenin-enriched Annona muricata Linn leaf extract by folic acid-conjugated and triphenylphosphonium-conjugated poly(glycerol adipate) nanoparticles to enhance toxicity against ovarian cancer cells.

The study demonstrated the fabrication of new poly(glycerol adipate) (PGA) nanoparticles decorated with folic acid (FOL-PGA) and triphenylphosphonium (TPP-PGA) and the potential on the delivery of acetogenin-enriched Annona muricata Linn leaf extract to ovarian cancer cells. FOL-PGA and TPP-PGA were successfully synthesized and used to fabricate FOL-decorated nanoparticles (FOL-NPs) and FOL-/TPP- decorated nanoparticles (FOL/TPP-NPs) by blending two polymers at a mass ratio of 1:1. All nanoparticles had small size of around 100 nm, narrow size distribution and high negative surface charge about -30 mV. The stable FOL/TPP-NPs showed highest drug loading of 14.9 ± 1.9% at 1:5 ratio of extract to polymer and reached to 35.8 ± 2.1% at higher ratio. Both nanoparticles released the extract in a biphasic sustained release manner over 5 days. The toxicity of the extract to SKOV3 cells was potentiated by FOL-NPs and FOL/TPP-NPs by 2.0 - 2.6 fold through induction of cell apoptosis. FOL/TPP-NPs showed lower IC50 and higher cellular uptake as compared to FOL-NPs. FOL-NPs exhibited folate receptor-mediated endocytosis. FOL/TPP-NPs provided more advantages than FOL-NPs in terms of stability in physiological fluid, uptake efficiency and targeting ability to mitochondria and showed a promising potential PGA platform for targeted delivery of herbal cytotoxic extracts.

Enhanced Production of Bryonolic Acid in Trichosanthes cucumerina L. (Thai Cultivar) Cell Cultures by Elicitors and Their Biological Activities.

Bryonolic acid is a triterpenoid compound found in cucurbitaceous roots. Due to its biological activities, this compound gets more attention to improve production. Herein, we carried out efficient ways with high bryonolic acid productions from Trichosanthes cucumerina L., a Thai medicinal plant utilizing plant cell cultures. The results showed that calli (24.65 ± 1.97 mg/g dry weight) and cell suspensions (15.69 ± 0.78 mg/g dry weight) exhibited the highest bryonolic acid productions compared with natural roots (approximately 2 mg/g dry weight). In the presence of three elicitors (methyl jasmonate, yeast extract, and chitosan), cell suspensions treated with 1 mg/mL of chitosan for eight days led to higher bryonolic acid contents (23.56 ± 1.68 mg/g dry weight). Interestingly, cell culture and root extracts with high bryonolic acid contents resulted in significantly higher percent cell viabilities than those observed under control (1% v/v DMSO) treatment in Saos-2 and MCF-7 cells. The present study indicated that T. cucumerina L. cell cultures are alternative and efficient to produce the biologically important secondary metabolite.

Screening and Matching Polymers with Drugs to Improve Drug Incorporation and Retention in Nanoparticles.

Key challenges hindering the clinical translation of the use of nanoparticles (NP) for delivery of drugs to tumors are inadequate drug loading and premature drug release. This study focused on understanding the conditions required to produce nanoparticles that can reach their target site with sufficient drug loading and drug retention for effective pharmacological action. Etoposide, etoposide phosphate, and teniposide were screened against modified poly(glycerol) adipate (PGA) based polymers by monitoring drug release from 40% drug in polymer films and using Fourier transform infrared spectroscopy (FTIR) and contact angle measurements to help understand the release results. Polymers were matched with the specific drugs based on the interactions observed. NP were then prepared by an interfacial deposition method. NPs were characterized and resulted in drug loadings ranging from 3.5% and 5%, respectively, for etoposide phosphate and etoposide with PGA modified with stearate (PGA85%C18) up to 13.4% for teniposide with PGA modified with tryptophan (PGA50%Try) and drug release of just 22-35% over 24 h. Assessment of cytotoxicity showed that etoposide nanoparticles with PGA85%C18 were more potent than an equivalent amount of free drug. This screening method to match polymers to drugs to monitor based drug and polymer interactions thus resulted in the formulation of nanoparticles with higher drug loading and slower release and potential for further development for clinical applications.

Synthesis and properties of a biodegradable polymer-drug conjugate: Methotrexate-poly(glycerol adipate).

Polymer-drug conjugates have been actively developed as potential anticancer drug delivery systems. In this study, we report the first polymer-anticancer drug conjugate with poly(glycerol adipate) (PGA) through the successful conjugation of methotrexate (MTX). MTX-PGA conjugates were controllably and simply fabricated by carbodiimide-mediated coupling reaction with various high molar ratios of MTX. The MTX-PGA conjugate self-assembled into nanoparticles with size dependent on the amount of conjugated MTX and the pH of medium. Change in particle size was attributed to steric hindrance and bulkiness inside the nanoparticle core and dissociation of free functional groups of the drug. The MTX-PGA nanoparticles were physically stable in media with pH range of 5-9 and ionic strength of up to 0.15 M NaCl and further chemically stable against hydrolysis in pH 7.4 medium over 30 days but enzymatically degradable to release unchanged free drug. Although 30%MTX-PGA nanoparticles exhibited only slightly less potency than free MTX in 791T cells in contrast to previously reported human serum albumin-MTX conjugates which had >300 times lower potency than free MTX. However, the MTX nanoparticles showed 7 times higher toxicity to Saos-2 cells than MTX. Together with the enzymic degradation experiments, these results suggest that with a suitable biodegradable polymer a linker moiety is not a necessary component. These easily synthesised PGA drug conjugates lacking a linker moiety could therefore be an effective new pathway for development of polymer drug conjugates.

ß-Cyclodextrin-based ternary complexes of haloperidol and organic acids: the effect of organic acids on the drug solubility enhancement.

Haloperidol (HALO) is a weak base with very low aqueous solubility that is used as an antipsychotic drug. This study aimed to improve its solubility by forming HALO/ß-cyclodextrin (ß-CD)-based ternary complexes with organic acids. The solubility of HALO/ß-CD binary and HALO/ß-CD/organic acid ternary complexes in different media (i.e. citrate buffer pH 3 and 6) was explored. The stoichiometric ratio between the drug and ß-CD was 1:1 in all complexes formed. The solubility of HALO/ß-CD binary complexes significantly increased in citrate buffer pH 3 compared with citrate buffer pH 6. For the ternary complexes, HALO/ß-CD/tartaric acid and HALO/ß-CD/lactic acid in citrate buffer pH 3 increased HALO solubility compared with HALO/ß-CD/succinic acid due to their higher unionized species. The highest stability constant and complexation efficiency values in citrate buffer pH 3 were shown by the ternary complexes with lactic acid followed by tartaric acid and succinic acid, respectively. Results indicated that lactic acid provided the greatest binding strength and solubilization efficiency for the complex.

Enhanced transmucosal delivery of itraconazole by thiolated d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate micelles for the treatment of Candida albicans.

This study aimed to investigate the transmucosal delivery of itraconazole (ITZ) by thiolated d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS-Cys) micelles. TPGS-Cys polymer was successfully synthesized by the simple coupling between carboxyl-activated TPGS and Cys as confirmed by NMR and FTIR techniques. Afterwards, the TPGS/TPGS-Cys micelles were prepared using the blend of TPGS and TPGS-Cys at 10:0, 7:3, 5:5, 3:7 and 0:10mass ratios. All micelles had the size ranged from 8 to 10nm with narrow size distribution and showed spherical in shape. The surface of the 10:0 TPGS micelles exhibited negatively charge while, the TPGS-Cys micelles demonstrated the slightly positive surface charge. The critical micelle concentration, loading capacity and release profiles of TPGS/TPGS-Cys micelles were comparable to the TPGS micelles. The release of ITZ from all micelles was biphasic and sustained in simulated saliva fluid over 48h. The 3:7 and 0:10 TPGS/TPGS-Cys micelles had a good mucoadhesive property. Meanwhile, only 0:10 TPGS/TPGS-Cys micelles enhanced the permeability through buccal mucosa and potentiated the antifungal activity of ITZ against Candida albicans by at least 1.35 folds as compared to ITZ alone. Therefore, this formulation can be further developed for the transmucosal delivery of ITZ for the treatment of C. albicans.

Investigation of cationized triblock and diblock poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers for oral delivery of enoxaparin: In vitro approach.

In this study, poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers grafted with a cationic ligand, propargyltrimethyl ammonium iodide (PTA), to fabricate the cationized triblock (P(CatCLCL)2-PEG) and diblock (P(CatCLCL)-mPEG) copolymers were investigated their potential use for oral delivery of enoxaparin (ENX). Influences of various PTA contents and different structures of the copolymers on molecular characteristics, ENX encapsulation, particle characteristics, and capability of drug transport across Caco-2 cells were elucidated. The results showed that P(CatCLCL)2-PEG and P(CatCLCL)-mPEG copolymers self-aggregated and encapsulated ENX into spherical particles of ∼200-450nm. The increasing amount of PTA on the copolymers increased encapsulation efficiency of over 90%. The ENX release from both types of the cationized copolymer particles was pH-dependent which was retarded at pH 1.2 and accelerated at pH 7.4, supporting the drug protection in the acidic environment and possible release in the blood circulation. The toxicity of ENX-loaded particles on Caco-2 cells decreased when decreasing the amount of PTA. The triblock and diblock particles dramatically enhanced ENX uptake and transport across Caco-2 cells as compared to the ENX solution. However, the different structures of the copolymers slightly affected ENX transport. These results suggested that P(CatCLCL)2-PEG and P(CatCLCL)-mPEG copolymers would be potential carriers for oral delivery of ENX. STATEMENT OF SIGNIFICANCE: The anionic drugs such as proteins, peptides or polysaccharides are generally administered via invasive route causing patient incompliance and high cost of hospitalization. The development of biomaterials for non-invasive delivery of those drugs has gained much attention, especially for oral delivery. However, they have limitation due to non-biocompatibility and poor drug bioavailability. In this study, the novel poly(ε-caprolactone)-co-poly(ethylene glycol) copolymers grafted with propargyltrimethyl ammonium iodide, a small cationic ligand, were introduced to use as a carrier for oral delivery of enoxaparin, a highly negatively charged drug. The study showed that these cationized copolymers could achieve high enoxaparin entrapment efficiency, protect drug release in an acidic environment and enhance enoxaparin permeability across Caco-2 cells, the intestinal cell model. These characteristics of the cationized copolymers make them a potential candidate for oral delivery of anionic drugs for biomaterial applications.

Self-aggregation of cationically modified poly(ε-caprolactone)2-co-poly(ethylene glycol) copolymers: Effect of cationic grafting ligand and poly(ε-caprolactone) chain length.

Cationic copolymers have been attractive to investigate due to their potential to complexation with anionic drugs and expected to use in the pharmaceutical application. In this study, the modified poly(ε-caprolactone)2-co-poly(ethylene glycol) copolymers (P(CL)2-PEG) were successfully synthesized by click reaction. The amount of small molecular cationic ligand, propargyltrimethyl ammonium iodide, was varied and grafted onto various mole ratios of P(CL) to PEG. The effects of P(CL) chain length and amount of the grafting cationic ligand on physicochemical properties of polymers and particles were studied. The number-average molecular weights of the copolymers grafted with cationic ligand were found ranging between 10,000 and 23,000g/mol as investigated by NMR. From DSC study, the results showed that the grafting ligand affected thermal behaviors of the copolymers by increasing the glass transition temperature and decreasing the melting temperature of the copolymers. Furthermore, these cationic copolymers could self-aggregate with their critical aggregation concentration depending on mole ratios of hydrophilic to hydrophobic portions. The particles containing higher amounts of the cationic ligand tended to aggregate in both acidic and basic pH environment and at high salt concentration. Additionally, particle size, size distribution (PdI), and morphology of self-assembling particles varied depending on P(CL) chain length and the amount of the grafting cationic ligand. The synthesized cationic copolymer showed a capability to encapsulate a high negatively charged drug, enoxaparin, with an encapsulation efficiency of 87%. After drug incorporation, the particles substantially changed in size, shape, PdI, and zeta potential to become more suitable for drug delivery. These cationic copolymers with flexible properties will be the candidate for further development as carriers for the delivery of negatively charged drugs.

Comparison of poly(ε-caprolactone) chain lengths of poly(ε-caprolactone)-co-d-α-tocopheryl-poly(ethylene glycol) 1000 succinate nanoparticles for enhancement of quercetin delivery to SKBR3 breast cancer cells.

This study aimed to investigate the effect of the different hydrophobic chain lengths of poly(ε-caprolactone)-co-d-α-tocopheryl polyethylene glycol 1000 succinate (P(CL)-TPGS) copolymers on the nanoparticle properties and delivery efficiency of quercetin to SKBR3 breast cancer cells. The 5:1, 10:1 and 20:1 P(CL)-TPGS copolymers were fabricated and found to be composed of 25.0%, 45.2% and 66.8% of hydrophobic P(CL) chains with respect to the polymer chain, respectively. The DSC measurement indicated the microphase separation of P(CL) and TPGS segments. The crystallization of P(CL) segment occurred when the P(CL) chain was higher than 25% due to the restricted mobility of P(CL) by TPGS. The longer P(CL) chain had the higher crystallinity while decreasing the crystallinity of TPGS segment. The increasing P(CL) chain length increased the particle size of P(CL)-TPGS nanoparticles from 20 to 205 nm and enhanced the loading capacity of quercetin due to the more hydrophobicity of the nanoparticle core. The release of quercetin was retarded by an increase in P(CL) chain length associated with the increasing hydrophobicity and crystallinity of P(CL)-TPGS copolymers. The P(CL)-TPGS nanoparticles potentiated the toxicity of quercetin to SKBR3 cells by at least 2.9 times compared to the quercetin solution. The cellular uptake of P(CL)-TPGS nanoparticles by SKBR3 cells occurred through cholesterol-dependent endocytosis. The 10:1 P(CL)-TPGS nanoparticles showed the highest toxicity and uptake efficiency and could be potentially used for the delivery of quercetin to breast cancer cells.

Properties of acyl modified poly(glycerol-adipate) comb-like polymers and their self-assembly into nanoparticles.

There is an increasing need to develop bio-compatible polymers with an increased range of different physicochemical properties. Poly(glycerol-adipate) (PGA) is a biocompatible, biodegradable amphiphilic polyester routinely produced from divinyl adipate and unprotected glycerol by an enzymatic route, bearing a hydroxyl group that can be further functionalized. Polymers with an average Mn of ∼13 kDa can be synthesized without any post-polymerization deprotection reactions. Acylated polymers with fatty acid chain length of C4, C8, and C18 (PGAB, PGAO, and PGAS, respectively) at different degrees of substitution were prepared. These modifications yield comb-like polymers that modulate the amphiphilic characteristics of PGA. This novel class of biocompatible polymers has been characterized through various techniques such as FT-IR, 1H NMR, surface, thermal analysis, and their ability to self-assemble into colloidal structures was evaluated by using DLS. The highly tunable properties of PGA reported herein demonstrate a biodegradable polymer platform, ideal for engineering solid dispersions, nanoemulsions, or nanoparticles for healthcare applications. © 2016 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 3267-3278.

Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate.

Folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-FOL) decorated methotrexate (MTX)-conjugated nanoparticles were developed for targeted delivery of MTX to folate receptor-expressed tumor cells. The synthesis of TPGS-FOL followed 3-step process. Firstly, the terminal hydroxyl group of TPGS was converted to sulfonyl chloride using mesyl chloride in comparison with nosyl and tosyl chlorides. The highest conversion efficiency and yield were obtained by mesyl chloride due to the formation of higher reactive intermediate in a presence of triethylamine. Secondly, the substitution of sulfonyl group by sodium azide produced considerably high yield with conversion efficiency of over 90%. Lastly, the coupling reaction of azido-substituted TPGS and propargyl folamide by click reaction resulted in 96% conjugation efficiency without polymer degradation. To fabricate the folate receptor-targeted nanoparticles, 10 and 20%mol MTX-conjugated PEGylated poly(ϵ-caprolactone) nanoparticles were decorated with TPGS-FOL. The size and size distribution of MTX-conjugated nanoparticles relatively increased with %MTX. The MTX release from the nanoparticles was accelerated in acidic medium with an increase of %MTX but retarded in physiological pH medium. The decoration of TPGS-FOL onto the nanoparticles slightly enlarged the size and size distribution of the nanoparticles; however, it did not affect the surface charge. The cytotoxicity and cellular uptake of MCF-7 cells demonstrated that 10% MTX-conjugated nanoparticles and FOL-decorated nanoparticles possessed higher toxicity and uptake efficiency than 20% MTX-conjugated nanoparticles and undecorated nanoparticles, respectively. The results indicated that FOL-10% MTX-conjugated nanoparticles exhibited potential targeted delivery of MTX to folate receptor-expressed cancer cells.

Investigation of pH Influence on Skin Permeation Behavior of Weak Acids Using Nonsteroidal Anti-Inflammatory Drugs.

As a continuing effort to understand the skin permeation behavior of weak acids and bases, the objectives of the present study were to evaluate skin permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) under the influence of pH, investigate the mechanism of pH effect, and examine a previous hypothesis that the effective skin pH for drug permeation is different from donor solution pH. In vitro permeability experiments were performed in side-by-side diffusion cells with diclofenac, ibuprofen, flurbiprofen, ketoprofen, and naproxen and human skin. The donor solution pH significantly affected skin permeation of NSAIDs, whereas no effect of the receiver pH was observed. Similar to previous observations, the apparent permeability coefficient versus donor solution pH relationships deviated from the predictions (fractions of unionized NSAIDs) according to the acid/base theory. The influences of the viable epidermis barrier, polar pathway transport, ion permeation across skin, and effective skin pH were investigated. The effective pH values for skin permeation determined using the NSAIDs (weak acids) in this study were different from those obtained previously with a weak base at the same donor solution pH conditions, suggesting that the observed permeability-pH relationships could not be explained solely by possible pH differences between skin and donor solution.

Investigation of pH Influence on Skin Permeation Behavior of Weak Acids Using Nonsteroidal Anti-Inflammatory Drugs.

As a continuing effort to understand the skin permeation behavior of weak acids and bases, the objectives of the present study were to evaluate skin permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) under the influence of pH, investigate the mechanism of pH effect, and examine a previous hypothesis that the effective skin pH for drug permeation is different from donor solution pH. In vitro permeability experiments were performed in side-by-side diffusion cells with diclofenac, ibuprofen, flurbiprofen, ketoprofen, and naproxen and human skin. The donor solution pH significantly affected skin permeation of NSAIDs, whereas no effect of the receiver pH was observed. Similar to previous observations, the apparent permeability coefficient versus donor solution pH relationships deviated from the predictions (fractions of unionized NSAIDs) according to the acid/base theory. The influences of the viable epidermis barrier, polar pathway transport, ion permeation across skin, and effective skin pH were investigated. The effective pH values for skin permeation determined using the NSAIDs (weak acids) in this study were different from those obtained previously with a weak base at the same donor solution pH conditions, suggesting that the observed permeability-pH relationships could not be explained solely by possible pH differences between skin and donor solution. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3459-3470, 2015.

Dissolution enhancement and in vitro performance of clarithromycin nanocrystals produced by precipitation-lyophilization-homogenization method.

The gastroduodenal diseases caused by Helicobacter pylori were commonly treated with antibiotic clarithromycin as a standard regimen. According to the poorly water-soluble of clarithromycin, the nanocrystal formulation was prepared. The aim of this study was to investigate an enhancement effect of clarithromycin nanocrystals produced by precipitation-lyophilization-homogenization (PLH) method on the saturation solubility, dissolution velocity, antibiotic activity, permeability through the gastric mucus and cellular permeability. Poloxamer 407 and sodium lauryl sulfate (SLS) were chosen as combined stabilizers in the nanocrystal system. The obtained clarithromycin nanocrystals were identified as cubic particles by SEM with a bulk population of approximately 400nm existed in crystalline and/or partial amorphous form as investigated by DSC and XRPD. The saturation solubility of the clarithromycin nanocrystals was increased by 1.5- and 6-folds higher than clarithromycin powder in buffer pH 5.0 and 6.8, respectively. The dissolution profiles of clarithromycin nanocrystals at pH 5.0 and 6.8 were significantly different from clarithromycin powder and the marketed product (f1 value >15 and f2 value <50). All dissolution parameters (relative dissolution rate, percent dissolution efficiency and mean dissolution time) showed that clarithromycin nanocrystals had higher dissolution rate when compared with the clarithromycin powder, the lyophilized coarse suspension and the marketed product. The bioassay study by diffusion agar method showed a maintained antibiotic activity of clarithromycin nanocrystals solubilized in buffer solution which was greater potency than the lyophilized coarse suspension and the clarithromycin powder. Additionally, the nanocrystals possessed higher permeability through gastric mucus and cellular monolayer of Caco-2 and NCI-N87 cells as compared to the lyophilized coarse suspension and the clarithromycin powder. The results indicated that, the developed clarithromycin nanocrystals were a potential delivery system that exerts more effectiveness in H. pylori eradication.

Development and characterization of lyophilized diazepam-loaded polymeric micelles.

Polymeric micelles were studied as delivery carriers of diazepam, a practically insoluble drug in water, for rectal administration. The diazepam-loaded polymeric micelles were developed by using poloxamer 407 (P407), poloxamer 188, and D-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS). Among the used polymers, TPGS resulted in polymeric micelles with good characteristics for encapsulation of diazepam which had the small particle size of 8-12 nm and narrow size distribution (PI 0.053-0.275). Additionally, 7.5% w/v of TPGS could entirely entrap the desired concentration of diazepam (5 mg/mL). To improve the physical stability upon lyophilization, an addition of P407 of 1% w/v prevented aggregation, increased physical stability, and maintained chemical stability of the lyophilized powders of diazepam-loaded polymeric micelles for 3 months storage at 4°C. The rate and amount of diazepam release from TPGS polymeric micelles mainly depended on the concentration of TPGS. The release data were fitted to Higuchi's model suggesting that the drug release mechanism was controlled by Fickian diffusion. In conclusion, 10% w/v TPGS and 1% w/v P407 were the optimum formulation of lyophilized diazepam-loaded polymeric micelles.