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

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

Foldable/Expandable Gastro-retentive Films Based on Starch and Chitosan as a Carrier For Prolonged Release of Resveratrol

Background: Resveratrol exerts a number of therapeutic effects, notably antiinflammatory, antioxidant and anti-cancer activities which are beneficial for the treatment of gastric diseases. However, the efficacy of resveratrol is severely limited due to the poor aqueous solubility and rapid metabolism following oral administration. As a result, foldable/expandable devices based on natural polymers merging with solid dispersion technology have been developed to increase the solubility, prolong the gastric residence time, and provide a controlled release therapy of resveratrol. Objectives: This research aimed to invent foldable/expandable films based on natural polymers, including starch and chitosan, for stomach-specific delivery and prolonged release of resveratrol. Methods: The films were prepared by solvent casting using either rice, tapioca, corn starch or pregelatinized corn starch combined with chitosan in different weight to weight ratios. Glycerol was included as a plasticizer. Resveratrol solid dispersions (Res-SD) prepared by solvent evaporation and employing PVP-K30 as a hydrophilic polymer were loaded into the polymeric film, which was subsequently folded prior to insertion in a hard gelatin capsule. Results: The solid dispersions improved the solubility of resveratrol by a factor of 500. All Res-SD loaded film formulations completely unfolded in simulated gastric fluid at 37oC within 10 min. Fluid absorption by the films was influenced by the ratio of amylose and amylopectin in the starch granules, with tapioca starch formulations displaying the highest fluid uptake. Films prepared from pregelatinized corn starch and chitosan resulted in highly efficient delivery of resveratrol, with more than 80%of the content released over a period of 12 hrs. Furthermore, the released polyphenol exhibited cytotoxic activity against human gastric adenocarcinoma cells and anti-inflammatory effects against lipopolysaccharide-stimulated murine, macrophage-like cells. Conclusions: These findings demonstrate the potential of foldable/expandable films based on natural polymers as a promising stomach-specific carrier for improving the treatment of gastric disorders. </jats:sec

Superporous hydrogels based on blends of chitosan and polyvinyl alcohol as a carrier for enhanced gastric delivery of resveratrol

Resveratrol exhibits a number of pharmacological properties, notably antioxidant, anti-inflammatory and anti-cancer activities which are beneficial for the treatment of gastric diseases. However, the poor aqueous solubility and rapid metabolism are the important limitations in clinical uses. Superporous hydrogels (SPHs) based on chitosan/PVA blends were developed as a carrier for resveratrol solid dispersion (Res_SD) to increase the solubility and achieve sustained drug release in the stomach. The SPHs were prepared by gas forming method using glyoxal and sodium bicarbonate as cross-linking agent and gas generator, respectively. The solid dispersions of resveratrol with PVP-K30 were prepared by solvent evaporation and incorporated into the superporous hydrogels. All formulations showed rapid absorption of simulated gastric fluid and reached the equilibrium swollen state within a few minutes. The water absorption ratio and mechanical strength of SPHs were predominantly affected by the chitosan content, with maximum values at 1400 % and 375 g/cm2, respectively.The Res_SD-loaded SPHs exhibited good floating properties and SEM micrographs revealed a highly interconnected pores structure with size around 150 μm. Resveratrol was efficiently entrapped within the SPHs at levels between 64 and 90 % w/w and efficient drug release was sustained over 12 h dependent on the concentration of chitosan and PVA. The Res_SD-loaded SPHs exhibited slightly less cytotoxic efffect towards AGS cells than pure resveratrol. Furthermore, the formulation showed similar anti-inflammatory activity against RAW 264.7 cells compared with indomethacin

High-Expansion Natural Composite Films for Controlled Delivery of Hydroxycitric Acid in Obesity Therapy

Expandable films represent a promising gastroretentive drug delivery system, offering prolonged gastric retention and sustained drug release features particularly advantageous for obesity treatment. This study developed high-expansion films using konjac and various low glycemic index starches, including purple potato, brown rice, resistant, and red jasmine rice starches, in combination with chitosan and hydroxypropyl methylcellulose (HPMC) E15. Garcinia extract was incorporated into the films using the solvent casting technique. Among 27 formulations, all demonstrated rapid unfolding (within 15 min) and significant expansion (2-4 folds). Hydroxycitric acid (HCA), the active component, was encapsulated at efficiencies exceeding 80% w/w. The konjac-based films exhibited favorable mechanical properties, expansion capacity, and drug content uniformity. Notably, the CK3-H1 formulation (2% w/v chitosan, 3% w/v konjac, 1% w/v HPMC E15) provided sustained HCA release over 8 h via diffusion. Cytotoxicity tests showed no toxic effects on RAW 264.7 macrophages at concentrations up to 400 &mu;g/mL. Furthermore, CK3-H1 achieved notable nitric oxide inhibition (35.80 &plusmn; 1.21%) and the highest reduction in lipid accumulation (31.09 &plusmn; 3.15%) in 3T3-L1 adipocytes, outperforming pure HCA and garcinia extract. These results suggest that expandable konjac-based films are a viable and effective delivery system for herbal anti-obesity agents

Development of Oral In Situ Gelling Liquid Formulations of Garcinia Extract for Treating Obesity

Novel in situ gelling liquid formulations incorporating garcinia extract were developed to achieve prolonged delivery of hydroxycitric acid (HCA), an active compound displaying anti-obesity function, following oral administration. The optimized formulation was composed of sodium alginate (1.5% w/v), hydroxypropyl methylcellulose (HPMC K100) (0.25% w/v), calcium carbonate (1% w/v) and garcinia extract (2% w/v). The formulation displayed rapid gelation in less than a minute on exposure to 0.1 N hydrochloric acid (pH 1.2) and remained afloat for more than 24 h. The formulations were capable of gradually releasing more than 80% of HCA load over 8 h, depending on the composition. The resulting gels exhibited high values of gel strength by texture analysis, suggesting they would offer resistance to breakdown under the action of stomach content movement. The optimized formulation loaded garcinia extract significantly reduced lipid accumulation in 3T3-L1 adipocyte cells and displayed moderate anti-inflammatory activity by inhibiting the production of nitric oxide (NO) in LPS-stimulated RAW 264.7 macrophage cells. These findings demonstrate that oral in situ gelling liquid formulations based on sodium alginate and HPMC K100 offer much potential for sustained delivery of HCA and other anti-obesity compounds

Development of Gastroretentive Carriers for Curcumin-Loaded Solid Dispersion Based on Expandable Starch/Chitosan Films

Curcumin, a polyphenolic extract from the rhizomes of turmeric, exhibits antioxidant, anti-inflammatory, and anticancer activities, which are beneficial for the treatment of gastric diseases. However, curcumin’s therapeutic usefulness is restricted by its low aqueous solubility and short gastric residence time. In this study, curcumin-loaded solid dispersion (ratio 1:5) was prepared using Eudragit® EPO (Cur EPO-SD), resulting in an approximately 12,000-fold increase in solubility to 6.38 mg/mL. Expandable films incorporating Cur EPO-SD were subsequently prepared by solvent casting using different types of starch (banana, corn, pregelatinized, and mung bean starch) in combination with chitosan. Films produced from banana, corn, pregelatinized and mung bean starch unfolded and expanded upon exposure to simulated gastric medium, resulting in sustained release of 80% of the curcumin content within 8 h, whereas films based on pregelatinized starch showed immediate release characteristics. Curcumin-loaded expandable films based on different types of starch exhibited similar cytotoxic effects toward AGS cells and more activity than unformulated curcumin. Furthermore, the films resulted in increased anti-inflammatory activity against RAW 264.7 macrophage cells compared with the NSAID, indomethacin. These findings demonstrate the potential of expandable curcumin-loaded films as gastroretentive dosage forms for the treatment of gastric diseases and to improve oral bioavailability.</jats:p